RBCC Red Blood Cell Collection

SNCA (NACP, PARK1) [Confidence: high (present in two of the MS resources)]
Alpha-synuclein (Non-A beta component of AD amyloid; Non-A4 component of amyloid precursor; NACP)

hRBCD IPI00024107
IPI00024107 Splice Isoform 1 Of Alpha-synuclein May be involved in the regulation of dopamine release and transport, expressed in low concentrations in all tissues except liver soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic Isoform 1, 2 or 3 found at its expected molecular weight found at molecular weight

UniProt P37840
ID SYUA_HUMAN Reviewed; 140 AA.
AC P37840; A8K2A4; Q13701; Q4JHI3; Q6IAU6;
DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1994, sequence version 1.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Alpha-synuclein;
DE AltName: Full=Non-A beta component of AD amyloid;
DE AltName: Full=Non-A4 component of amyloid precursor;
DE Short=NACP;
GN Name=SNCA; Synonyms=NACP, PARK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 61-95.
RC TISSUE=Brain;
RX PubMed=8248242; DOI=10.1073/pnas.90.23.11282;
RA Ueda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M.,
RA Otero D.A., Kondo J., Ihara Y., Saitoh T.;
RT "Molecular cloning of cDNA encoding an unrecognized component of
RT amyloid in Alzheimer disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:11282-11286(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2-4 AND 2-5).
RX PubMed=7601450; DOI=10.1016/0888-7543(95)80208-4;
RA Campion D., Martin C., Heilig R., Charbonnier F., Moreau V.,
RA Flaman J.-M., Petit J.-L., Hannequin D., Brice A., Frebourg T.;
RT "The NACP/synuclein gene: chromosomal assignment and screening for
RT alterations in Alzheimer disease.";
RL Genomics 26:254-257(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2-4).
RC TISSUE=Brain;
RX PubMed=7802671; DOI=10.1006/bbrc.1994.2816;
RA Ueda K., Saitoh T., Mori H.;
RT "Tissue-dependent alternative splicing of mRNA for NACP, the precursor
RT of non-A beta component of Alzheimer's disease amyloid.";
RL Biochem. Biophys. Res. Commun. 205:1366-1372(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Xia Y., Silva R.D., Chen X.H., Saitoh T.;
RL Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2-4).
RX PubMed=11156617; DOI=10.1101/gr.165801;
RA Touchman J.W., Dehejia A., Chiba-Falek O., Cabin D.E., Schwartz J.R.,
RA Orrison B.M., Polymeropoulos M.H., Nussbaum R.L.;
RT "Human and mouse alpha-synuclein genes: comparative genomic sequence
RT analysis and identification of a novel gene regulatory element.";
RL Genome Res. 11:78-86(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Hu X., Xu Y., Peng X., Yuan J., Qiang B.;
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP PROTEIN SEQUENCE OF 59-96, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [13]
RP PHOSPHORYLATION BY CASEIN KINASE.
RX PubMed=10617630; DOI=10.1074/jbc.275.1.390;
RA Okochi M., Walter J., Koyama A., Nakajo S., Baba M., Iwatsubo T.,
RA Meijer L., Kahle P.J., Haass C.;
RT "Constitutive phosphorylation of the Parkinson's disease associated
RT alpha-synuclein.";
RL J. Biol. Chem. 275:390-397(2000).
RN [14]
RP PHOSPHORYLATION BY G-PROTEIN COUPLED RECEPTOR KINASE.
RX PubMed=10852916; DOI=10.1074/jbc.M003542200;
RA Pronin A.N., Morris A.J., Surguchov A., Benovic J.L.;
RT "Synucleins are a novel class of substrates for G protein-coupled
RT receptor kinases.";
RL J. Biol. Chem. 275:26515-26522(2000).
RN [15]
RP PHOSPHORYLATION AT TYR-125 BY FYN.
RX PubMed=11162638; DOI=10.1006/bbrc.2000.4253;
RA Nakamura T., Yamashita H., Takahashi T., Nakamura S.;
RT "Activated Fyn phosphorylates alpha-synuclein at tyrosine residue
RT 125.";
RL Biochem. Biophys. Res. Commun. 280:1085-1092(2001).
RN [16]
RP INTERACTION WITH PHOSPHOLIPASE D.
RX PubMed=11821392; DOI=10.1074/jbc.M110414200;
RA Ahn B.H., Rhim H., Kim S.Y., Sung Y.M., Lee M.Y., Choi J.Y.,
RA Wolozin B., Chang J.S., Lee Y.H., Kwon T.K., Chung K.C., Yoon S.H.,
RA Hahn S.J., Kim M.S., Jo Y.H., Min do S.;
RT "Alpha-synuclein interacts with phospholipase D isozymes and inhibits
RT pervanadate-induced phospholipase D activation in human embryonic
RT kidney-293 cells.";
RL J. Biol. Chem. 277:12334-12342(2002).
RN [17]
RP PHOSPHORYLATION AT SER-129.
RX PubMed=11813001; DOI=10.1038/ncb748;
RA Fujiwara H., Hasegawa M., Dohmae N., Kawashima A., Masliah E.,
RA Goldberg M.S., Shen J., Takio K., Iwatsubo T.;
RT "alpha-Synuclein is phosphorylated in synucleinopathy lesions.";
RL Nat. Cell Biol. 4:160-164(2002).
RN [18]
RP INTERACTION WITH HISTONES, AND SUBCELLULAR LOCATION.
RX PubMed=12859192; DOI=10.1021/bi0341152;
RA Goers J., Manning-Bog A.B., McCormack A.L., Millett I.S., Doniach S.,
RA Di Monte D.A., Uversky V.N., Fink A.L.;
RT "Nuclear localization of alpha-synuclein and its interaction with
RT histones.";
RL Biochemistry 42:8465-8471(2003).
RN [19]
RP ROLE OF THE C-TERMINUS IN FIBRILLOGENESIS.
RX PubMed=12859200; DOI=10.1021/bi027363r;
RA Murray I.V., Giasson B.I., Quinn S.M., Koppaka V., Axelsen P.H.,
RA Ischiropoulos H., Trojanowski J.Q., Lee V.M.;
RT "Role of alpha-synuclein carboxy-terminus on fibril formation in
RT vitro.";
RL Biochemistry 42:8530-8540(2003).
RN [20]
RP REVIEW.
RX PubMed=12558071;
RA Alves da Costa C.;
RT "Recent advances on alpha-synuclein cell biology: functions and
RT dysfunctions.";
RL Curr. Mol. Med. 3:17-24(2003).
RN [21]
RP MUTAGENESIS OF TYR-39; TYR-125; TYR-133 AND TYR-136, CHARACTERIZATION
RP OF VARIANT THR-53, AND PHOSPHORYLATION AT TYR-125.
RX PubMed=12893833; DOI=10.1074/jbc.M213217200;
RA Takahashi T., Yamashita H., Nagano Y., Nakamura T., Ohmori H.,
RA Avraham H., Avraham S., Yasuda M., Matsumoto M.;
RT "Identification and characterization of a novel Pyk2/related adhesion
RT focal tyrosine kinase-associated protein that inhibits alpha-synuclein
RT phosphorylation.";
RL J. Biol. Chem. 278:42225-42233(2003).
RN [22]
RP SUBCELLULAR LOCATION.
RX PubMed=15282274; DOI=10.1523/JNEUROSCI.1594-04.2004;
RA Fortin D.L., Troyer M.D., Nakamura K., Kubo S., Anthony M.D.,
RA Edwards R.H.;
RT "Lipid rafts mediate the synaptic localization of alpha-synuclein.";
RL J. Neurosci. 24:6715-6723(2004).
RN [23]
RP FIBRILS FORMATION, DOMAIN NAC, AND MUTAGENESIS OF 67-GLY--VAL-71;
RP 71-VAL--VAL-82; 76-ALA-VAL-77; VAL-77; ALA-78 AND 85-ALA--PHE-94.
RX PubMed=19722699; DOI=10.1021/bi900539p;
RA Waxman E.A., Mazzulli J.R., Giasson B.I.;
RT "Characterization of hydrophobic residue requirements for alpha-
RT synuclein fibrillization.";
RL Biochemistry 48:9427-9436(2009).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP COPPER-BINDING, AND MUTAGENESIS OF ASP-2 AND HIS-50.
RX PubMed=21319811; DOI=10.1021/bi101912q;
RA Dudzik C.G., Walter E.D., Millhauser G.L.;
RT "Coordination features and affinity of the Cu(2)+ site in the alpha-
RT synuclein protein of Parkinson's disease.";
RL Biochemistry 50:1771-1777(2011).
RN [26]
RP ACETYLATION AT MET-1.
RX PubMed=22407793; DOI=10.1002/pro.2056;
RA Trexler A.J., Rhoades E.;
RT "N-Terminal acetylation is critical for forming alpha-helical oligomer
RT of alpha-synuclein.";
RL Protein Sci. 21:601-605(2012).
RN [27]
RP STRUCTURE BY NMR IN COMPLEX WITH DETERGENT MICELLES.
RX PubMed=15615727; DOI=10.1074/jbc.M411805200;
RA Ulmer T.S., Bax A., Cole N.B., Nussbaum R.L.;
RT "Structure and dynamics of micelle-bound human alpha-synuclein.";
RL J. Biol. Chem. 280:9595-9603(2005).
RN [28]
RP VARIANT PARK1 THR-53.
RX PubMed=9197268; DOI=10.1126/science.276.5321.2045;
RA Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A.,
RA Dutra A., Pike B., Root H., Rubenstein J., Boyer R., Stenroos E.S.,
RA Chandrasekharappa S., Athanassiadou A., Papapetropoulos T.,
RA Johnson W.G., Lazzarini A.M., Duvoisin R.C., di Iorio G., Golbe L.I.,
RA Nussbaum R.L.;
RT "Mutation in the alpha-synuclein gene identified in families with
RT Parkinson's disease.";
RL Science 276:2045-2047(1997).
RN [29]
RP VARIANT PARK1 PRO-30.
RX PubMed=9462735; DOI=10.1038/ng0298-106;
RA Krueger R., Kuhn W., Mueller T., Woitalla D., Graeber M., Koesel S.,
RA Przuntek H., Epplen J.T., Schoels L., Riess O.;
RT "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's
RT disease.";
RL Nat. Genet. 18:106-108(1998).
RN [30]
RP VARIANT PARK1/DLB LYS-46.
RX PubMed=14755719; DOI=10.1002/ana.10795;
RA Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R.,
RA Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B.,
RA Llorens V., Gomez Tortosa E., del Ser T., Munoz D.G., de Yebenes J.G.;
RT "The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy
RT body dementia.";
RL Ann. Neurol. 55:164-173(2004).
RN [31]
RP CHARACTERIZATION OF VARIANT LYS-46.
RX PubMed=15498564; DOI=10.1016/j.febslet.2004.09.038;
RA Choi W., Zibaee S., Jakes R., Serpell L.C., Davletov B.,
RA Crowther R.A., Goedert M.;
RT "Mutation E46K increases phospholipid binding and assembly into
RT filaments of human alpha-synuclein.";
RL FEBS Lett. 576:363-368(2004).
RN [32]
RP VARIANT PARK1 GLN-50.
RX PubMed=23457019; DOI=10.1002/mds.25421;
RA Appel-Cresswell S., Vilarino-Guell C., Encarnacion M., Sherman H.,
RA Yu I., Shah B., Weir D., Thompson C., Szu-Tu C., Trinh J., Aasly J.O.,
RA Rajput A., Rajput A.H., Jon Stoessl A., Farrer M.J.;
RT "Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's
RT disease.";
RL Mov. Disord. 28:811-813(2013).
RN [33]
RP VARIANT PARK1 GLN-50, AND CHARACTERIZATION OF VARIANT PARK1 GLN-50.
RX PubMed=23427326; DOI=10.1212/WNL.0b013e31828727ba;
RA Proukakis C., Dudzik C.G., Brier T., MacKay D.S., Cooper J.M.,
RA Millhauser G.L., Houlden H., Schapira A.H.;
RT "A novel alpha-synuclein missense mutation in Parkinson disease.";
RL Neurology 80:1062-1064(2013).
CC -!- FUNCTION: May be involved in the regulation of dopamine release
CC and transport. Induces fibrillization of microtubule-associated
CC protein tau. Reduces neuronal responsiveness to various apoptotic
CC stimuli, leading to a decreased caspase-3 activation.
CC -!- SUBUNIT: Soluble monomer which can form filamentous aggregates.
CC Interacts with UCHL1 (By similarity). Interacts with phospholipase
CC D and histones.
CC -!- INTERACTION:
CC Self; NbExp=26; IntAct=EBI-985879, EBI-985879;
CC P49841:GSK3B; NbExp=2; IntAct=EBI-985879, EBI-373586;
CC P08107:HSPA1B; NbExp=7; IntAct=EBI-985879, EBI-629985;
CC P42858:HTT; NbExp=4; IntAct=EBI-985879, EBI-466029;
CC Q5S007:LRRK2; NbExp=6; IntAct=EBI-985879, EBI-5323863;
CC P10636-8:MAPT; NbExp=3; IntAct=EBI-985879, EBI-366233;
CC Q9UI14:RABAC1; NbExp=4; IntAct=EBI-985879, EBI-712367;
CC Q01959:SLC6A3; NbExp=3; IntAct=EBI-985879, EBI-6661445;
CC Q61327:Slc6a3 (xeno); NbExp=5; IntAct=EBI-985879, EBI-7839708;
CC P17600:SYN1; NbExp=2; IntAct=EBI-985879, EBI-717274;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane. Nucleus. Cell junction,
CC synapse. Note=Membrane-bound in dopaminergic neurons.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Additional isoforms seem to exist;
CC Name=1; Synonyms=NACP140;
CC IsoId=P37840-1; Sequence=Displayed;
CC Name=2-4; Synonyms=NACP112;
CC IsoId=P37840-2; Sequence=VSP_006364;
CC Name=2-5;
CC IsoId=P37840-3; Sequence=VSP_006363;
CC -!- TISSUE SPECIFICITY: Expressed principally in brain but is also
CC expressed in low concentrations in all tissues examined except in
CC liver. Concentrated in presynaptic nerve terminals.
CC -!- DOMAIN: The 'non A-beta component of Alzheimer disease amyloid
CC plaque' domain (NAC domain) is involved in fibrils formation. The
CC middle hydrophobic region forms the core of the filaments. The C-
CC terminus may regulate aggregation and determine the diameter of
CC the filaments.
CC -!- PTM: Phosphorylated, predominantly on serine residues.
CC Phosphorylation by CK1 appears to occur on residues distinct from
CC the residue phosphorylated by other kinases. Phosphorylation of
CC Ser-129 is selective and extensive in synucleinopathy lesions. In
CC vitro, phosphorylation at Ser-129 promoted insoluble fibril
CC formation. Phosphorylated on Tyr-125 by a PTK2B-dependent pathway
CC upon osmotic stress.
CC -!- PTM: Hallmark lesions of neurodegenerative synucleinopathies
CC contain alpha-synuclein that is modified by nitration of tyrosine
CC residues and possibly by dityrosine cross-linking to generated
CC stable oligomers.
CC -!- PTM: Ubiquitinated. The predominant conjugate is the
CC diubiquitinated form (By similarity).
CC -!- PTM: Acetylation at Met-1 seems to be important for proper folding
CC and native oligomeric structure.
CC -!- DISEASE: Note=Genetic alterations of SNCA resulting in aberrant
CC polymerization into fibrils, are associated with several
CC neurodegenerative diseases (synucleinopathies). SNCA fibrillar
CC aggregates represent the major non A-beta component of Alzheimer
CC disease amyloid plaque, and a major component of Lewy body
CC inclusions. They are also found within Lewy body (LB)-like
CC intraneuronal inclusions, glial inclusions and axonal spheroids in
CC neurodegeneration with brain iron accumulation type 1.
CC -!- DISEASE: Parkinson disease 1 (PARK1) [MIM:168601]: A complex
CC neurodegenerative disorder characterized by bradykinesia, resting
CC tremor, muscular rigidity and postural instability. Additional
CC features are characteristic postural abnormalities, dysautonomia,
CC dystonic cramps, and dementia. The pathology of Parkinson disease
CC involves the loss of dopaminergic neurons in the substantia nigra
CC and the presence of Lewy bodies (intraneuronal accumulations of
CC aggregated proteins), in surviving neurons in various areas of the
CC brain. The disease is progressive and usually manifests after the
CC age of 50 years, although early-onset cases (before 50 years) are
CC known. The majority of the cases are sporadic suggesting a
CC multifactorial etiology based on environmental and genetic
CC factors. However, some patients present with a positive family
CC history for the disease. Familial forms of the disease usually
CC begin at earlier ages and are associated with atypical clinical
CC features. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Parkinson disease 4 (PARK4) [MIM:605543]: A complex
CC neurodegenerative disorder with manifestations ranging from
CC typical Parkinson disease to dementia with Lewy bodies. Clinical
CC features include parkinsonian symptoms (resting tremor, rigidity,
CC postural instability and bradykinesia), dementia, diffuse Lewy
CC body pathology, autonomic dysfunction, hallucinations and
CC paranoia. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Dementia Lewy body (DLB) [MIM:127750]: A
CC neurodegenerative disorder characterized by mental impairment
CC leading to dementia, parkinsonism, fluctuating cognitive function,
CC visual hallucinations, falls, syncopal episodes, and sensitivity
CC to neuroleptic medication. Brainstem or cortical intraneuronal
CC accumulations of aggregated proteins (Lewy bodies) are the only
CC essential pathologic features. Patients may also have hippocampal
CC and neocortical senile plaques, sometimes in sufficient number to
CC fulfill the diagnostic criteria for Alzheimer disease. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the synuclein family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SNCA";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/snca/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L08850; AAA16117.1; -; mRNA.
DR EMBL; L36674; AAA98493.1; -; mRNA.
DR EMBL; L36675; AAA98487.1; -; mRNA.
DR EMBL; D31839; BAA06625.1; -; mRNA.
DR EMBL; U46901; AAC02114.1; -; Genomic_DNA.
DR EMBL; U46897; AAC02114.1; JOINED; Genomic_DNA.
DR EMBL; U46898; AAC02114.1; JOINED; Genomic_DNA.
DR EMBL; U46899; AAC02114.1; JOINED; Genomic_DNA.
DR EMBL; AF163864; AAG30302.1; -; Genomic_DNA.
DR EMBL; AF163864; AAG30303.1; -; Genomic_DNA.
DR EMBL; AY049786; AAL15443.1; -; mRNA.
DR EMBL; AK290169; BAF82858.1; -; mRNA.
DR EMBL; CR457058; CAG33339.1; -; mRNA.
DR EMBL; DQ088379; AAY88735.1; -; Genomic_DNA.
DR EMBL; CH471057; EAX06036.1; -; Genomic_DNA.
DR EMBL; BC013293; AAH13293.1; -; mRNA.
DR EMBL; BC108275; AAI08276.1; -; mRNA.
DR PIR; A49669; A49669.
DR PIR; S56746; S56746.
DR RefSeq; NP_000336.1; NM_000345.3.
DR RefSeq; NP_001139526.1; NM_001146054.1.
DR RefSeq; NP_001139527.1; NM_001146055.1.
DR RefSeq; NP_009292.1; NM_007308.2.
DR RefSeq; XP_005263239.1; XM_005263182.1.
DR RefSeq; XP_005263240.1; XM_005263183.1.
DR RefSeq; XP_005263241.1; XM_005263184.1.
DR RefSeq; XP_005263242.1; XM_005263185.1.
DR RefSeq; XP_005263243.1; XM_005263186.1.
DR RefSeq; XP_005263244.1; XM_005263187.1.
DR RefSeq; XP_005263245.1; XM_005263188.1.
DR RefSeq; XP_005263246.1; XM_005263189.1.
DR UniGene; Hs.21374; -.
DR PDB; 1XQ8; NMR; -; A=1-140.
DR PDB; 2JN5; NMR; -; A=1-12.
DR PDB; 2KKW; NMR; -; A=1-140.
DR PDB; 2M55; NMR; -; B=1-19.
DR PDB; 2X6M; X-ray; 1.62 A; B=132-140.
DR PDB; 3Q25; X-ray; 1.90 A; A=1-19.
DR PDB; 3Q26; X-ray; 1.54 A; A=9-42.
DR PDB; 3Q27; X-ray; 1.30 A; A=32-57.
DR PDB; 3Q28; X-ray; 1.60 A; A=58-79.
DR PDB; 3Q29; X-ray; 2.30 A; A/C=1-19.
DR PDBsum; 1XQ8; -.
DR PDBsum; 2JN5; -.
DR PDBsum; 2KKW; -.
DR PDBsum; 2M55; -.
DR PDBsum; 2X6M; -.
DR PDBsum; 3Q25; -.
DR PDBsum; 3Q26; -.
DR PDBsum; 3Q27; -.
DR PDBsum; 3Q28; -.
DR PDBsum; 3Q29; -.
DR DisProt; DP00070; -.
DR ProteinModelPortal; P37840; -.
DR SMR; P37840; 1-140.
DR DIP; DIP-35354N; -.
DR IntAct; P37840; 206.
DR MINT; MINT-2515483; -.
DR STRING; 9606.ENSP00000338345; -.
DR ChEMBL; CHEMBL6152; -.
DR DrugBank; DB01065; Melatonin.
DR TCDB; 1.C.77.1.1; the synuclein (synuclein) family.
DR PhosphoSite; P37840; -.
DR DMDM; 586067; -.
DR PaxDb; P37840; -.
DR PRIDE; P37840; -.
DR DNASU; 6622; -.
DR Ensembl; ENST00000336904; ENSP00000338345; ENSG00000145335.
DR Ensembl; ENST00000345009; ENSP00000343683; ENSG00000145335.
DR Ensembl; ENST00000394986; ENSP00000378437; ENSG00000145335.
DR Ensembl; ENST00000394989; ENSP00000378440; ENSG00000145335.
DR Ensembl; ENST00000394991; ENSP00000378442; ENSG00000145335.
DR Ensembl; ENST00000420646; ENSP00000396241; ENSG00000145335.
DR Ensembl; ENST00000505199; ENSP00000421485; ENSG00000145335.
DR Ensembl; ENST00000506244; ENSP00000422238; ENSG00000145335.
DR Ensembl; ENST00000508895; ENSP00000426955; ENSG00000145335.
DR GeneID; 6622; -.
DR KEGG; hsa:6622; -.
DR UCSC; uc003hsp.3; human.
DR CTD; 6622; -.
DR GeneCards; GC04M090646; -.
DR HGNC; HGNC:11138; SNCA.
DR HPA; CAB010877; -.
DR HPA; HPA005459; -.
DR MIM; 127750; phenotype.
DR MIM; 163890; gene.
DR MIM; 168600; phenotype.
DR MIM; 168601; phenotype.
DR MIM; 605543; phenotype.
DR neXtProt; NX_P37840; -.
DR Orphanet; 1648; Dementia with Lewy body.
DR Orphanet; 171695; Parkinsonian-pyramidal syndrome.
DR Orphanet; 2828; Young adult-onset Parkinsonism.
DR PharmGKB; PA35986; -.
DR eggNOG; NOG44393; -.
DR HOGENOM; HOG000008691; -.
DR HOVERGEN; HBG000481; -.
DR InParanoid; P37840; -.
DR KO; K04528; -.
DR OMA; SEAYEMP; -.
DR OrthoDB; EOG7034KG; -.
DR Reactome; REACT_116125; Disease.
DR SignaLink; P37840; -.
DR ChiTaRS; SNCA; human.
DR EvolutionaryTrace; P37840; -.
DR GeneWiki; Alpha-synuclein; -.
DR GenomeRNAi; 6622; -.
DR NextBio; 25791; -.
DR PMAP-CutDB; P37840; -.
DR PRO; PR:P37840; -.
DR ArrayExpress; P37840; -.
DR Bgee; P37840; -.
DR CleanEx; HS_SNCA; -.
DR Genevestigator; P37840; -.
DR GO; GO:0015629; C:actin cytoskeleton; IDA:UniProtKB.
DR GO; GO:0030424; C:axon; IDA:UniProtKB.
DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0043205; C:fibril; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0030426; C:growth cone; IDA:UniProtKB.
DR GO; GO:0016234; C:inclusion body; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005640; C:nuclear outer membrane; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005840; C:ribosome; IEA:Ensembl.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0005507; F:copper ion binding; IDA:UniProtKB.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB.
DR GO; GO:0042393; F:histone binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0005543; F:phospholipid binding; IEA:Ensembl.
DR GO; GO:0051219; F:phosphoprotein binding; IDA:BHF-UCL.
DR GO; GO:0048156; F:tau protein binding; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:BHF-UCL.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0048148; P:behavioral response to cocaine; IEA:Ensembl.
DR GO; GO:0071280; P:cellular response to copper ion; IDA:UniProtKB.
DR GO; GO:0071872; P:cellular response to epinephrine stimulus; TAS:UniProtKB.
DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; IEA:Ensembl.
DR GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl.
DR GO; GO:0042416; P:dopamine biosynthetic process; TAS:UniProtKB.
DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; TAS:UniProtKB.
DR GO; GO:0043206; P:extracellular fibril organization; TAS:UniProtKB.
DR GO; GO:0006631; P:fatty acid metabolic process; IEA:Ensembl.
DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl.
DR GO; GO:0001774; P:microglial cell activation; IEA:Ensembl.
DR GO; GO:0042775; P:mitochondrial ATP synthesis coupled electron transport; IEA:Ensembl.
DR GO; GO:0007006; P:mitochondrial membrane organization; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0045963; P:negative regulation of dopamine metabolic process; IEA:Ensembl.
DR GO; GO:0051585; P:negative regulation of dopamine uptake involved in synaptic transmission; IDA:UniProtKB.
DR GO; GO:0045920; P:negative regulation of exocytosis; IMP:UniProtKB.
DR GO; GO:0035067; P:negative regulation of histone acetylation; IDA:UniProtKB.
DR GO; GO:0031115; P:negative regulation of microtubule polymerization; IDA:BHF-UCL.
DR GO; GO:0032769; P:negative regulation of monooxygenase activity; IDA:BHF-UCL.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0051622; P:negative regulation of norepinephrine uptake; IDA:UniProtKB.
DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0051612; P:negative regulation of serotonin uptake; IDA:UniProtKB.
DR GO; GO:0070495; P:negative regulation of thrombin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0032410; P:negative regulation of transporter activity; IDA:UniProtKB.
DR GO; GO:0006638; P:neutral lipid metabolic process; IEA:Ensembl.
DR GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl.
DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:UniProtKB.
DR GO; GO:0060732; P:positive regulation of inositol phosphate biosynthetic process; IDA:UniProtKB.
DR GO; GO:0001956; P:positive regulation of neurotransmitter secretion; IEA:Ensembl.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISS:BHF-UCL.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:BHF-UCL.
DR GO; GO:0001921; P:positive regulation of receptor recycling; IDA:UniProtKB.
DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:UniProtKB.
DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB.
DR GO; GO:0031623; P:receptor internalization; IDA:UniProtKB.
DR GO; GO:0050812; P:regulation of acyl-CoA biosynthetic process; IEA:Ensembl.
DR GO; GO:0014059; P:regulation of dopamine secretion; TAS:UniProtKB.
DR GO; GO:0060079; P:regulation of excitatory postsynaptic membrane potential; IEA:Ensembl.
DR GO; GO:0014048; P:regulation of glutamate secretion; IEA:Ensembl.
DR GO; GO:0040012; P:regulation of locomotion; IEA:Ensembl.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0043030; P:regulation of macrophage activation; IEA:Ensembl.
DR GO; GO:0010517; P:regulation of phospholipase activity; IDA:UniProtKB.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0034341; P:response to interferon-gamma; IDA:UniProtKB.
DR GO; GO:0070555; P:response to interleukin-1; IDA:UniProtKB.
DR GO; GO:0010040; P:response to iron(II) ion; IDA:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:UniProtKB.
DR GO; GO:0032026; P:response to magnesium ion; IDA:UniProtKB.
DR GO; GO:0050808; P:synapse organization; IEA:Ensembl.
DR GO; GO:0048488; P:synaptic vesicle endocytosis; ISS:UniProtKB.
DR Gene3D; 1.10.287.700; -; 1.
DR InterPro; IPR001058; Synuclein.
DR InterPro; IPR002460; Synuclein_alpha.
DR PANTHER; PTHR13820; PTHR13820; 1.
DR Pfam; PF01387; Synuclein; 1.
DR PRINTS; PR01212; ASYNUCLEIN.
DR PRINTS; PR01211; SYNUCLEIN.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Alzheimer disease;
KW Amyloid; Cell junction; Complete proteome; Copper; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Membrane; Metal-binding;
KW Neurodegeneration; Nucleus; Parkinson disease; Parkinsonism;
KW Phosphoprotein; Reference proteome; Repeat; Synapse; Ubl conjugation.
FT CHAIN 1 140 Alpha-synuclein.
FT /FTId=PRO_0000184022.
FT REPEAT 20 30 1.
FT REPEAT 31 41 2.
FT REPEAT 42 56 3; approximate.
FT REPEAT 57 67 4.
FT REGION 20 67 4 X 11 AA tandem repeats of [EGS]-K-T-K-
FT [EQ]-[GQ]-V-X(4).
FT METAL 2 2 Copper (Probable).
FT METAL 50 50 Copper (Probable).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 87 87 Phosphoserine; by CK2.
FT MOD_RES 125 125 Phosphotyrosine; by FYN.
FT MOD_RES 129 129 Phosphoserine; by BARK1, CK2 and GRK5;
FT alternate.
FT MOD_RES 129 129 Phosphoserine; by PLK2; alternate.
FT VAR_SEQ 41 54 Missing (in isoform 2-5).
FT /FTId=VSP_006363.
FT VAR_SEQ 103 130 Missing (in isoform 2-4).
FT /FTId=VSP_006364.
FT VARIANT 30 30 A -> P (in PARK1).
FT /FTId=VAR_007957.
FT VARIANT 46 46 E -> K (in PARK1 and DLB; significant
FT increase in binding to negatively charged
FT phospholipid liposomes).
FT /FTId=VAR_022703.
FT VARIANT 50 50 H -> Q (in PARK1; impairs copper-
FT binding).
FT /FTId=VAR_070171.
FT VARIANT 53 53 A -> T (in PARK1; no effect on osmotic
FT stress-induced phosphorylation).
FT /FTId=VAR_007454.
FT MUTAGEN 2 2 D->A: Impairs copper-binding.
FT MUTAGEN 39 39 Y->F: No effect on osmotic stress-induced
FT phosphorylation.
FT MUTAGEN 50 50 H->A: Impairs copper-binding.
FT MUTAGEN 67 71 Missing: Reduces polymerization into
FT amyloid fibrils.
FT MUTAGEN 71 82 Missing: Impairs polymerization into
FT amyloid fibrils.
FT MUTAGEN 76 77 Missing: Impairs polymerization into
FT amyloid fibrils.
FT MUTAGEN 76 76 Missing: Does not affect polymerization
FT into amyloid fibrils.
FT MUTAGEN 77 77 Missing: Does not affect polymerization
FT into amyloid fibrils.
FT MUTAGEN 78 78 Missing: Does not affect polymerization
FT into amyloid fibrils.
FT MUTAGEN 85 94 Missing: Reduces polymerization into
FT amyloid fibrils.
FT MUTAGEN 125 125 Y->F: Abolishes osmotic stress-induced
FT phosphorylation.
FT MUTAGEN 133 133 Y->F: No effect on osmotic stress-induced
FT phosphorylation.
FT MUTAGEN 136 136 Y->F: No effect on osmotic stress-induced
FT phosphorylation.
FT HELIX 3 11
FT HELIX 21 32
FT HELIX 41 44
FT HELIX 52 55
FT HELIX 66 68
FT STRAND 110 113
FT TURN 120 122
FT TURN 124 126
SQ SEQUENCE 140 AA; 14460 MW; 6BB2F12128931663 CRC64;
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK
EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP
DNEAYEMPSE EGYQDYEPEA
//

MIM 127750
*RECORD*
*FIELD* NO
127750
*FIELD* TI
#127750 DEMENTIA, LEWY BODY; DLB
;;LEWY BODY DEMENTIA;;
DIFFUSE LEWY BODY DISEASE
DIFFUSE LEWY BODY DISEASE WITH GAZE PALSY, INCLUDED;;
read moreLEWY BODY VARIANT OF ALZHEIMER DISEASE, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because dementia with Lewy
bodies (DLB) can be caused by mutation in the alpha-synuclein (SNCA;
163890) or beta-synuclein (SNCB; 602569) genes.

Familial Parkinson disease-1 (PARK1; 168601) is associated with mutation
in the SNCA gene.

The epsilon-4 allele of the APOE gene (107741) and the B allele of the
CYP2D6 gene (124030), a cytochrome P-450 monooxygenase, have also been
implicated in DLB.

A mutation in the prion protein gene (PRNP; see 176640.0017) has been
identified in 1 patient with DLB. Some patients with a diagnosis
consistent with Lewy body disease or dementia have mutations in the
LRRK2 gene (609007), which is associated with Parkinson disease-8
(PARK8; 607060) (Giasson et al., 2006; Ross et al., 2006).

One family with a mutation in the PSEN2 gene (600759.0009), usually
associated with Alzheimer disease-4 (AD4; 606889), had clinical and
neuropathologic findings consistent with DLB (Piscopo et al., 2008).

DESCRIPTION

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder
clinically characterized by dementia and parkinsonism, often with
fluctuating cognitive function, visual hallucinations, falls, syncopal
episodes, and sensitivity to neuroleptic medication. Pathologically,
Lewy bodies are present in a pattern more widespread than usually
observed in Parkinson disease (see PD; 168600). Alzheimer disease (AD;
104300)-associated pathology and spongiform changes may also be seen
(McKeith et al., 1996; Mizutani, 2000; McKeith et al., 2005).

CLINICAL FEATURES

Ishikawa et al. (1997) reported 2 unrelated families with familial
autosomal dominant diffuse Lewy body disease. In family A, 4 patients
over 3 generations presented with parkinsonism, vertical ocular
limitation, progressive dementia, and delusions or visual
hallucinations. Two of the patients developed neuroleptic malignant
syndrome (NMS). Family S had 3 affected members over 3 generations. One
was examined in detail and presented with parkinsonism and progressive
dementia and later developed NMS. In a member of family S reported by
Ishikawa et al. (1997), Ishikawa et al. (2005) identified a mutation in
the PSEN1 gene (104311.0032). No mutations were identified in the SNCA
gene. The phenotype was an overlap between DLB and Alzheimer disease
with spastic paraparesis (607822).

Denson et al. (1997) reported 10 individuals with Lewy body disease in 3
successive generations of 2 closely intermarried families. The phenotype
was variable: 4 patients displayed parkinsonian features only, 3 had
dementia only, and 3 had combined parkinsonism and dementia. Mean age of
onset was 62 years. Linkage studies were inconclusive.

Wakabayashi et al. (1998) described a Japanese family with parkinsonism
and later-onset dementia. The proband developed parkinsonism at the age
of 61 years, followed by dementia starting when she was 67. Her uncle,
who was also her husband, died at the age of 78 years after 7- and
5-year histories of parkinsonism and dementia, respectively. Her 2 sons
developed similar parkinsonism at the ages of 39 and 28 years and also
suffered later-onset dementia. The apolipoprotein E genotype of the
proband, her uncle, and 1 of their sons was E3/4 and that of the other
son was E4/4. The authors concluded that this represented autosomal
dominant diffuse Lewy body disease.

Ohara et al. (1999) presented a familial case of dementia with Lewy
bodies in 3 sibs, born of first-cousin parents, who demonstrated
progressive dementia with a progressive language disorder characterized
by dysarthria, paraphasia, and difficulty in finding words. The 2
brothers presented with parkinsonism and fluctuating cognition. The
sister and one of the brothers also had visual hallucinations. No
mutations in the alpha-synuclein gene (SNCA; 163890), the parkin gene
(PARK2; 602544), or the ubiquitin carboxyl-terminal esterase L1 gene
(UCHL1; 191342) were found.

Graeber and Muller (2003) provided a review of DLB, which they stated is
the second most common degenerative dementia after Alzheimer disease.
Clinically, DLB differs from Alzheimer disease in that disease symptoms
are prone to fluctuate and patients often suffer from visual
hallucinations, though short-term memory is relatively preserved. As
many as 70% of patients have parkinsonism and up to 50% are sensitive to
the extrapyramidal side effects of neuroleptic drugs. Graeber and Muller
(2003) suggested that DLB is a complex disorder with both genetic and
environmental factors involved in the pathogenesis, as is the case for
many common disorders.

Ohtake et al. (2004) reported a patient with DLB and a mutation in the
SNCB gene (602569.0002). He presented at age 64 years with a 3-year
history of mild dementia and deterioration in his handwriting. He had
frontal lobe involvement manifesting as executive and language
dysfunction. He later developed depression, motor apraxia, parkinsonism,
and audio and visual hallucinations. Neuropathologic examination showed
extensive Lewy bodies in the hippocampus, amygdala, and substantia
nigra. Several family members were affected or possibly affected in an
autosomal dominant pattern of inheritance.

- Pathologic Findings

Khachaturian (1985) performed an autopsy series of elderly individuals
with dementia and found that the second most common pathology after the
senile plaques and neurofibrillary tangles of Alzheimer disease was that
of Lewy bodies found in subcortical and cortical regions. Patients with
such 'Lewy body dementia' also have a sufficient number of hippocampal
and neocortical senile plaques to meet the diagnostic criteria for
Alzheimer disease. Hansen et al. (1990) referred to such patients as
having the 'Lewy body variant of Alzheimer disease.' The term 'diffuse
Lewy body disease' is reserved for patients with brainstem and cortical
Lewy bodies but an insufficient number of senile plaques to fulfill the
diagnostic criteria for Alzheimer disease.

Wakabayashi et al. (1998) reported that pathologic examination of their
2 patients showed marked neuronal loss with Lewy bodies in the
brainstem, pigmented nuclei, and numerous cortical Lewy bodies and
ubiquitin-positive hippocampal neurites. Brain examination of 1 patient
studied by Ishikawa et al. (1997) showed neuronal loss with gliosis and
many Lewy bodies in the cerebral cortex and brainstem. One affected
individual from the kindred reported by Denson et al. (1997) showed
neuronal loss and gliosis as well as many Lewy bodies throughout the
cerebral cortex and brainstem. Neurofibrillary tangles and neuritic
plaques were present, but rare. Neuropathology of the proband reported
by Ohara et al. (1999) demonstrated numerous Lewy bodies in the cerebral
cortex and brain stem, with no neurofibrillary tangles or neuritic
plaques.

Obi et al. (2008) reported the neuropathologic findings of a Japanese
patient with PD and later-onset dementia who was heterozygous for a
duplication of the SNCA gene (163890.0005) (Nishioka et al., 2006). The
patient presented with classic levodopa-responsive parkinsonism at age
47. Loss of memory, visual hallucinations, and progressive cognitive
decline began at age 60. Brain MRI showed medial temporal lobe atrophy
on both sides, and single photon emission computed tomography (SPECT)
showed hypoperfusion of the frontotemporal and occipital lobes. He later
became bedridden and died of pneumonia at age 67. Postmortem examination
showed mild frontal lobe atrophy and severe depigmentation of the
substantia nigra and locus ceruleus. Severe neuronal loss was noted in
the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus
nerve, the amygdala, and the CA2/3 of the hippocampus.
SNCA-immunostaining revealed multiple Lewy bodies in the cerebral
cortex, hippocampus, and brainstem. The Lewy body-related pathology was
graded as diffuse neocortical type based on the pathologic
classification of dementia with Lewy bodies.

- Diffuse Lewy Body Disease with Gaze Palsy

Lewis and Gawel (1990) and Fearnley et al. (1991) each presented a case
report in which a patient (71 and 76 years old) with dementia and
parkinsonism also presented with horizontal and vertical supranuclear
gaze palsy, prompting an initial diagnosis of progressive supranuclear
palsy (PSP; 601104). Pathologic diagnosis in both cases revealed diffuse
Lewy body disease with Lewy bodies in areas believed to be associated
with gaze control.

De Bruin et al. (1992) reported a 67-year-old man with a family history
of parkinsonism who presented with supranuclear gaze palsy and later
developed parkinsonism and mental impairment. A diagnosis of PSP was
made initially, but postmortem pathologic examination revealed diffuse
Lewy body disease with multiple Lewy bodies in the neocortex and
brainstem, as well as lesser numbers of neuritic plaques and
neurofibrillary tangles.

Brett et al. (2002) reported 2 sibs with onset in their 60s of a
disorder characterized by parkinsonism, dementia, and visual
hallucinations, which progressed to incapacity. One patient exhibited
vertical supranuclear gaze palsy, and the other patient could not be
tested. Pathologic examination of both cases showed diffuse Lewy body
disease, with changes in the posterior commissure, the rostral
interstitial nucleus of the medial longitudinal fasciculus, and the
interstitial nucleus of Cajal, areas that subserve vertical gaze.

DIAGNOSIS

The International Consortium on Dementia with Lewy bodies in 1995
established guidelines for the clinical and pathologic diagnosis of DLB.
Mental impairment leading to dementia is the central core feature, with
fluctuation in cognitive function, visual hallucinations, and motor
features of parkinsonism being other key symptoms. Brainstem or cortical
Lewy bodies are the only essential pathologic features, although other
pathologic changes may be present as well (McKeith et al., 1996). The
guidelines were updated in 2005 (McKeith et al., 2005) to include sleep
disturbances, neuroleptic sensitivity, reduced striatal dopamine
transporter activity on functional neuroimaging, and pathologic grading.

MOLECULAR GENETICS

- SNCA Gene

Zarranz et al. (2004) reported a Spanish family with autosomal dominant
parkinsonism and dementia with Lewy bodies, diagnosed using strict
criteria. Neuropathologic examination showed diffuse distribution of
Lewy bodies in cortical and subcortical areas. Molecular analysis
identified a mutation in the SNCA gene (163890.0004) that cosegregated
with the disease phenotype. Zarranz et al. (2004) noted that because
there is clinical and pathologic overlap between PD and DLB, the
distinction and/or relationship between the 2 disorders is difficult to
discern.

In affected members of 1 of the Japanese families reported by Ishikawa
et al. (1997) with early-onset parkinsonism and dementia, Ikeuchi et al.
(2008) identified a duplication of the SNCA gene (163809.0005). Three
patients were heterozygous for the duplication, and 1 was homozygous for
the duplication, having 4 copies of the SNCA gene. The entire
duplication segment spanned 5 Mb and included at least 10 neighboring
genes. The homozygous patient showed earlier onset and earlier death,
with more severe cognitive impairment.

Uchiyama et al. (2008) reported a Japanese mother and son with
duplication of the SNCA gene associated with variable features of
parkinsonism and dementia. The son had prominent parkinsonism in his
late forties, followed by fluctuating cognitive decline, visual
hallucinations, and deficits in verbal fluency a few years later. The
mother presented later at age 72 with memory disturbances and
fluctuating cognitive deficits. She then developed mild parkinsonism and
visual hallucinations. PET studies showed that both patients had diffuse
hypometabolism in the brain that extended to the occipital visual cortex
in the mother. Uchiyama et al. (2008) noted that the diagnoses in the
son and mother were compatible with PD dementia and Lewy body dementia,
respectively.

- SNCB Gene

In 2 unrelated patients with dementia with Lewy bodies, 1 of whom had a
family history of the disorder, Ohtake et al. (2004) identified 2
different heterozygous mutations in the SNCB gene (602569.0001;
602569.0002). Ohtake et al. (2004) postulated that an alteration in SNCB
may impair its normal inhibitory action on the formation of toxic
alpha-synuclein fibrils, thereby indirectly contributing to disease
pathogenesis.

- PRNP Gene

In a 55-year-old man with slowly progressive dementia, dysarthria, gait
disturbance, and rigidity, but no myoclonus or EEG abnormalities, Koide
et al. (2002) identified a heterozygous met232-to-arg mutation in the
PRNP gene (M232R; 176640.0017). The patient was given a preliminary
diagnosis of Creutzfeldt-Jakob disease (CJD; 123400). However,
postmortem brain examination showed many Lewy bodies in the substantia
nigra and cerebral cortices as well as lack of prion protein
immunoreactivity, and final diagnosis was dementia with Lewy bodies.

- Gene Associations

Galasko et al. (1994) analyzed the frequency of the apolipoprotein
epsilon-4 allele (APOE4) in 74 subjects with Alzheimer disease, 40
patients with the Lewy body variant of Alzheimer disease, and 8 with
diffuse Lewy body disease. The APOE4 allele frequency was 39.6% in pure
Alzheimer disease, 29% in the Lewy body variant of Alzheimer disease,
and only 6.25% in the 8 patients with diffuse Lewy body disease. Galasko
et al. (1994) argued that this further supported their conclusion that
dementia in the Lewy body variant is caused by the Alzheimer disease
lesions, whereas the cause of the dementia in diffuse Lewy body disease
is distinct.

Saitoh et al. (1995) analyzed the allele frequency of debrisoquine
4-hydroxylase (CYP2D6; 124030.0001) in an autopsy series consisting of
all Caucasian samples. Forty-four of these had Lewy body dementia, which
they defined as meeting neuropathologic criteria for Alzheimer disease,
having at least 1 Lewy body, and having a primary clinical manifestation
of dementia rather than Parkinson disease. In addition, there were 83
controls who had pure Alzheimer disease and 37 controls who had dementia
without Alzheimer disease. The CYP2D6B allele frequency in Lewy body
dementia was 0.307, considerably higher than the 0.163 allele frequency
in pure Alzheimer disease and the 0.122 frequency in non-Alzheimer
disease dementia. Saitoh et al. (1995) suggested that the CYP2D6B allele
is a risk factor for Lewy body disease, and that this may have
therapeutic implications.

Beyer et al. (2008) found different disease-specific expression of
isoforms of the SNCA, PARK2, and synphilin-1 (SNCAIP; 603779) genes in
frontal lobe cortices from patients with 4 diseases: pure Lewy body
dementia, so-called 'common' Lewy body disease, in which amyloid plaques
can also be seen, Parkinson disease, and Alzheimer disease. The data
indicated that each disease can be characterized by its own molecular
mechanisms and that different molecular mechanisms can lead to the
development of similar neuropathologic changes.

Goker-Alpan et al. (2006) identified heterozygous mutations in the
glucocerebrosidase gene (GBA; 606463) in 8 (23%) of 35 patients with
dementia with Lewy bodies. The authors postulated that a mutant GBA
enzyme may take on a different and unexpected role that may contribute
to the development of synucleinopathies. In 2 (3.5%) of 57 European
patients with Lewy body dementia, Mata et al. (2008) identified
heterozygous mutations in the GBA gene: 1 patient had the L444P mutation
(606463.0001), and the other had the N370S mutation (606463.0003). The
authors estimated that the population-attributable risk for GBA
mutations in Lewy body disorders was only about 3% in patients of
European ancestry.

*FIELD* RF
1. Beyer, K.; Domingo-Sabat, M.; Humbert, J.; Carrato, C.; Ferrer,
I.; Ariza, A.: Differential expression of alpha-synuclein, parkin,
and synphilin-1 isoforms in Lewy body disease. Neurogenetics 9:
163-172, 2008.

2. Brett, F. M.; Henson, C.; Staunton, H.: Familial diffuse Lewy
body disease, eye movement abnormalities, and distribution of pathology. Arch.
Neurol. 59: 464-467, 2002.

3. de Bruin, V. M. S.; Lees, A. J.; Daniel, S. E.: Diffuse Lewy body
disease presenting with supranuclear gaze palsy, parkinsonism, and
dementia: a case report. Mov. Disord. 7: 355-358, 1992.

4. Denson, M. A.; Wszolek, Z. K.; Pfeiffer, R. F.; Wszolek, E. K.;
Paschall, T. M.; McComb, R. D.: Familial parkinsonism, dementia,
and Lewy body disease: study of family G. Ann. Neurol. 42: 638-643,
1997.

5. Fearnley, J. M.; Revesz, T.; Brooks, D. J.; Frackowiak, R. S. J.;
Lees, A. J.: Diffuse Lewy body disease presenting with a supranuclear
gaze palsy. J. Neurol. Neurosurg. Psychiat. 54: 159-161, 1991.

6. Galasko, D.; Saitoh, T.; Xia, Y.; Thal, L. J.; Katzman, R.; Hill,
L. R.; Hansen, L.: The apolipoprotein E allele epsilon-4 is overrepresented
in patients with the Lewy body variant of Alzheimer's disease. Neurology 44:
1950-1951, 1994.

7. Giasson, B. I.; Covy, J. P.; Bonini, N. M.; Hurtig, H. I.; Farrer,
M. J.; Trojanowski, J. Q.; Van Deerlin, V. M.: Biochemical and pathological
characterization of Lrrk2. Ann. Neurol. 59: 315-322, 2006.

8. Goker-Alpan, O.; Giasson, B. I.; Eblan, M. J.; Nguyen, J.; Hurtig,
H. I.; Lee, V. M.-Y.; Trojanowski, J. Q.; Sidransky, E.: Glucocerebrosidase
mutations are an important risk factor for Lewy body disorders. Neurology 67:
908-910, 2006.

9. Graeber, M. B.; Muller, U.: Dementia with Lewy bodies: disease
concept and genetics. Neurogenetics 4: 157-162, 2003.

10. Hansen, L.; Salmon, D.; Galasko, D.; Masliah, E.; Katzman, R.;
DeTeresa, R.; Thal, L.; Pay, M. M.; Hofstetter, R.; Klauber, M.; Rice,
V.; Butters, N.; Alford, M.: The Lewy body variant of Alzheimer's
disease: a clinical and pathologic entity. Neurology 40: 1-8, 1990.

11. Ikeuchi, T.; Kakita, A.; Shiga, A.; Kasuga, K.; Kaneko, H.; Tan,
C.-F.; Idezuka, J.; Wakabayashi, K.; Onodera, O.; Iwatsubo, T.; Nishizawa,
M.; Takahashi, H.; Ishikawa, A.: Patients homozygous and heterozygous
for SNCA duplication in a family with parkinsonism and dementia. Arch.
Neurol. 65: 514-519, 2008.

12. Ishikawa, A.; Piao, Y.-S.; Miyashita, A.; Kuwano, R.; Onodera,
O.; Ohtake, H.; Suzuki, M.; Nishizawa, M.; Takahashi, H.: A mutant
PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann.
Neurol. 57: 429-434, 2005.

13. Ishikawa, A.; Takahashi, H.; Tanaka, H.; Hayashi, T.; Tsuji, S.
: Clinical features of familial diffuse Lewy body disease. Europ.
Neurol. 38 (suppl. 1): 34-38, 1997.

14. Khachaturian, Z. S.: Diagnosis of Alzheimer's disease. Arch.
Neurol. 42: 1097-1105, 1985.

15. Koide, T.; Ohtake, H.; Nakajima, T.; Furukawa, H.; Sakai, K.;
Kamei, H.; Makifuchi, T.; Fukuhara, N.: A patient with dementia with
Lewy bodies and codon 232 mutation of PRNP. Neurology 59: 1619-1621,
2002.

16. Lewis, A. J.; Gawel, M. J.: Diffuse Lewy body disease with dementia
and oculomotor dysfunction. Mov. Disord. 5: 143-147, 1990.

17. Mata, I. F.; Samii, A.; Schneer, S. H.; Roberts, J. W.; Griffith,
A.; Leis, B. C.; Schellenberg, G. D.; Sidransky, E.; Bird, T. D.;
Leverenz, J. B.; Tsuang, D.; Zabetian, C. P.: Glucocerebrosidase
gene mutations: a risk factor for Lewy body disorders. Arch. Neurol. 65:
379-382, 2008.

18. McKeith, I. G.; Dickson, D. W.; Lowe, J.; Emre, M.; O'Brien, J.
T.; Feldman, H.; Cummings, J.; Duda, J. E.; Lippa, C.; Perry, E. K.;
Aarsland, D.; Arai, H.; and 33 others: Diagnosis and management
of dementia with Lewy bodies: third report of the DLB consortium. Neurology 65:
1863-1872, 2005. Note: Erratum: Neurology 65: 1992 only, 2005.

19. McKeith, I. G.; Galasko, D.; Kosaka, K.; Perry, E. K.; Dickson,
D. W.; Hansen, L. A.; Salmon, D. P.; Lowe, J.; Mirra, S. S.; Byrne,
E. J.; Lennox, G.; Quinn, N. P.; Edwardson, J. A.; Ince, P. G.; Bergeron,
C.; Burns, A.; Miller, B. L.; Lovestone, S.; Collerton, D.; Jansen,
E. N.; Ballard, C.; de Vos, R. A.; Wilcock, G. K.; Jellinger, K. A.;
Perry, R. H.: Consensus guidelines for the clinical and pathologic
diagnosis of dementia with Lewy bodies (DLB): report of the consortium
on DLB international workshop. Neurology 47: 1113-1124, 1996.

20. Mizutani, T.: Diagnostic criteria of diffuse Lewy body disease. Nippon
Rinsho 58: 2044-2048, 2000.

21. Nishioka, K.; Hayashi, S.; Farrer, M. J.; Singleton, A. B.; Yoshino,
H.; Imai, H.; Kitami, T.; Sato, K.; Kuroda, R.; Tomiyama, H.; Mizoguchi,
K.; Murata, M.; Toda, T.; Imoto, I.; Inazawa, J.; Mizuno, Y.; Hattori,
N.: Clinical heterogeneity of alpha-synuclein gene duplication in
Parkinson's disease. Ann. Neurol. 59: 298-309, 2006.

22. Obi, T.; Nishioka, K.; Ross, O. A.; Terada, T.; Yamazaki, K.;
Sugiura, A.; Takanashi, M.; Mizoguchi, K.; Mori, H.; Mizuno, Y.; Hattori,
N.: Clinicopathologic study of a SNCA gene duplication patient with
parkinson disease and dementia. Neurology 70: 238-241, 2008.

23. Ohara, K.; Takauchi, S.; Kokai, M.; Morimura, Y.; Nakajima, T.;
Morita, Y.: Familial dementia with Lewy bodies (DLB). Clin. Neuropathol. 18:
232-239, 1999.

24. Ohtake, H.; Limprasert, P.; Fan, Y.; Onodera, O.; Kakita, A.;
Takahashi, H.; Bonner, L. T.; Tsuang, D. W.; Murray, I. V. J.; Lee,
V. M.-Y.; Trojanowski, J. Q.; Ishikawa, A.; Idezuka, J.; Murata, M.;
Toda, T.; Bird, T. D.; Leverenz, J. B.; Tsuji, S.; La Spada, A. R.
: Beta-synuclein gene alterations in dementia with Lewy bodies. Neurology 63:
805-811, 2004.

25. Piscopo, P.; Marcon, G.; Piras, M. R.; Crestini, A.; Campeggi,
L. M.; Deiana, E.; Cherchi, R.; Tanda, F.; Deplano, A.; Vanacore,
N.; Tagliavini, F.; Pocchiari, M.; Giaccone, G.; Confaloni, A.: A
novel PSEN2 mutation associated with a peculiar phenotype. Neurology 70:
1549-1554, 2008.

26. Ross, O. A.; Toft, M.; Whittle, A. J.; Johnson, J. L.; Papapetropoulos,
S.; Mash, D. C.; Litvan, I.; Gordon, M. F.; Wszolek, Z. K.; Farrer,
M. J.; Dickson, D. W.: Lrrk2 and Lewy body disease. Ann. Neurol. 59:
388-393, 2006.

27. Saitoh, T.; Xia, Y.; Chen, X.; Masliah, E.; Galasko, D.; Shults,
C.; Thal, L. J.; Hansen, L. A.; Katzman, R.: The CYP2D6B mutant allele
is overrepresented in the Lewy body variant of Alzheimer's disease. Ann.
Neurol. 37: 110-112, 1995.

28. Uchiyama, T.; Ikeuchi, T.; Ouchi, Y.; Sakamoto, M.; Kasuga, K.;
Shiga, A.; Suzuki, M.; Ito, M.; Atsumi, T.; Shimizu, T.; Ohashi, T.
: Prominent psychiatric symptoms and glucose hypometabolism in a family
with a SNCA duplication. Neurology 71: 1289-1290, 2008.

29. Wakabayashi, K.; Hayashi, S.; Ishikawa, A.; Hayashi, T.; Okuizumi,
K.; Tanaka, H.; Tsuji, S.; Takahashi, H.: Autosomal dominant diffuse
Lewy body disease. Acta Neuropath. 96: 207-210, 1998.

30. Zarranz, J. J.; Alegre, J.; Gomez-Esteban, J. C.; Lezcano, E.;
Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atares,
B.; Llorens, V.; Gomez Tortosa, E.; del Ser, T.; Munoz, D. G.; de
Yebenes, J. G.: The new mutation, E46K, of alpha-synuclein causes
parkinson and Lewy body dementia. Ann. Neurol. 55: 164-173, 2004.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Visual hallucinations;
Delusions;
Progressive dementia;
Fluctuations in consciousness;
Sensitivity to neuroleptic medication;
Diffuse Lewy bodies throughout the brain (cortical and subcortical
regions)

MISCELLANEOUS:
Onset in the sixth or seventh decades;
Phenotypic overlap with Parkinson disease;
Allelic disorder to Parkinson disease-1 (PARK1, 168601)

MOLECULAR BASIS:
Caused by mutation in the alpha-synuclein gene (SNCA, 163890.0004);
Caused by mutation in the beta-synuclein gene (SNCB, 602569.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 06/13/2005
Cassandra L. Kniffin - revised: 6/4/2004

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 06/13/2005
joanna: 8/17/2004
ckniffin: 6/4/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 3/27/2009
Cassandra L. Kniffin - updated: 2/3/2009
Cassandra L. Kniffin - updated: 1/9/2009
Cassandra L. Kniffin - updated: 11/3/2008
Cassandra L. Kniffin - updated: 10/1/2008
Cassandra L. Kniffin - updated: 8/3/2007
Cassandra L. Kniffin - updated: 4/20/2006
Cassandra L. Kniffin - updated: 7/25/2005
Cassandra L. Kniffin - updated: 6/13/2005
Cassandra L. Kniffin - updated: 6/4/2004
Victor A. McKusick - updated: 10/13/2003
Cassandra L. Kniffin - updated: 1/22/2003
Cassandra L. Kniffin - reorganized: 10/14/2002
Cassandra L. Kniffin - updated: 10/10/2002
Orest Hurko - updated: 9/27/1995

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 12/21/2012
terry: 4/26/2011
ckniffin: 3/24/2011
wwang: 4/7/2009
ckniffin: 3/27/2009
wwang: 2/9/2009
ckniffin: 2/3/2009
wwang: 1/15/2009
ckniffin: 1/9/2009
wwang: 11/10/2008
ckniffin: 11/3/2008
wwang: 10/1/2008
ckniffin: 10/1/2008
wwang: 8/17/2007
ckniffin: 8/3/2007
wwang: 4/25/2006
ckniffin: 4/20/2006
ckniffin: 7/25/2005
wwang: 6/16/2005
ckniffin: 6/13/2005
terry: 2/22/2005
tkritzer: 6/11/2004
ckniffin: 6/4/2004
tkritzer: 10/14/2003
tkritzer: 10/13/2003
carol: 2/4/2003
tkritzer: 1/28/2003
ckniffin: 1/22/2003
ckniffin: 1/16/2003
carol: 1/14/2003
ckniffin: 10/14/2002
carol: 10/14/2002
ckniffin: 10/14/2002
ckniffin: 10/10/2002
alopez: 10/23/2000
terry: 6/3/1998
joanna: 4/21/1998
carol: 1/13/1995
mimadm: 6/25/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

MIM 163890
*RECORD*
*FIELD* NO
163890
*FIELD* TI
*163890 SYNUCLEIN, ALPHA; SNCA
;;NON-A-BETA COMPONENT OF ALZHEIMER DISEASE AMYLOID, PRECURSOR OF; NACP;;
read moreNON-A4 COMPONENT OF AMYLOID, PRECURSOR OF
*FIELD* TX

DESCRIPTION

Alpha-synuclein is a highly conserved protein that is abundant in
neurons, especially presynaptic terminals. Aggregated alpha-synuclein
proteins form brain lesions that are hallmarks of neurodegenerative
synucleinopathies (summary by Giasson et al., 2000).

CLONING

A neuropathologic hallmark of Alzheimer disease (104300) is widespread
amyloid deposition. Analyzing the entire amino acid sequence in an
amyloid preparation, Ueda et al. (1993) found, in addition to the major
A-beta fragment (104760), 2 unknown peptides. They raised antibodies
against synthetic peptides using subsequences of the peptides. These
antibodies immunostained amyloid in neuritic and diffuse plaques as well
as vascular amyloid. Electron microscopic study demonstrated that the
immunostaining was localized on amyloid fibrils. Ueda et al. (1993)
isolated an apparently full-length cDNA encoding a 140-amino acid
protein within which 2 previously unreported amyloid sequences were
encoded in tandem in the mouse hydrophobic domain. They tentatively
named the 35-amino acid peptide NAC (for non-A-beta component of AD
amyloid) and its precursor NACP. Secondary structure predicted that the
NAC peptide sequence has a strong tendency to form beta-structures
consistent with its association with amyloid. NACP was detected as a
protein of molecular mass 19,000 in the cytosolic fraction of brain
homogenates and comigrated on immunoblots with NACP synthesized in E.
coli from NACP cDNA. NACP mRNA was expressed principally in brain but
also in low concentrations in all tissues examined except in liver.

Campion et al. (1995) found by a computer search of protein sequence
databases that NACP is the human counterpart of rat synuclein (Maroteaux
and Scheller, 1991), with which it shares 95% sequence homology. Rat
synuclein is specifically expressed in brain and is associated with
synaptosomal membranes in neurons.

Campion et al. (1995) cloned 3 alternatively spliced transcripts in
lymphocytes derived from a normal subject. Beyer et al. (2008) noted
that there are at least 3 SNCA mRNA transcript variants generated by
alternative splicing: SNCA140, which is the whole and main transcript,
and SNCA112 and SNCA126, which result from in-frame deletions of exons 3
and 5, respectively. They identified a fourth transcript, SNCA98, which
lacks exons 3 and 5 and is expressed at varying levels specifically in
fetal and adult human brain.

Jakes et al. (1994) identified 2 distinct synucleins in human brain,
alpha-synuclein and beta-synuclein (602569). They suggested that there
may be a family of synucleins.

Nakai et al. (2007) found expression of Snca in murine bone marrow,
including in erythroblasts and megakaryocytes. Snca was also present in
reticulocytes and circulating erythroid cells. However, Snca-null mice
showed no hematologic abnormalities. A 20-kD monomer of SNCA was
detected in human erythrocytes.

Scherzer et al. (2008) found high SNCA expression in normal red blood
cells during the terminal steps of erythrocyte differentiation,
including reticulocytes. SNCA was strongly coexpression and coinduced
with critical enzymes of heme metabolism, including ALAS2 (301300), FECH
(612386), and BLVRB (600941). Using this information, Scherzer et al.
(2008) determined that expression of the SNCA gene in reticulocytes is
regulated by the transcription factor GATA1 (305371), which specifically
occupies a conserved region within intron 1 of the SNCA gene and can
induce a 6.9-fold increase in alpha-synuclein protein. Endogenous GATA2
(137295), which is highly expressed in substantia nigra, also occupies
intron 1 of the SNCA gene and modulates SNCA expression in dopaminergic
cells.

GENE STRUCTURE

Touchman et al. (2001) determined that the SNCA gene contains 6 exons
and spans about 117 kb. Using transient transfection of a luciferase
reporter construct, they determined that a simple upstream repeat is
required for normal expression of SNCA. A similar, but not identical,
repeat is located in the promoter region of the mouse Snca gene.

MAPPING

Hartz (2010) mapped the SNCA gene to chromosome 4q22.1 based on an
alignment of the SNCA sequence (GenBank GENBANK L36675) with the genomic
sequence (GRCh37).

Campion et al. (1995) mapped the NACP/synuclein gene to chromosome 4.
Chen et al. (1995) mapped the NACP gene to 4q21.3-q22 by PCR-based
analysis of human/rodent hybrid cells and by fluorescence in situ
hybridization (FISH). Shibasaki et al. (1995) isolated a cosmid clone
containing the SNCA gene and mapped it to 4q21.3-q22 by FISH.
Spillantini et al. (1995) also used PCR panels and fluorescence in situ
hybridization to map the SNCA gene to human chromosome 4q21.

Touchman et al. (2001) mapped the mouse Snca gene to chromosome 6,
between the genes for Atoh2 and Atoh1 (601461).

GENE FUNCTION

Jakes et al. (1994) used immunohistochemistry to show that
alpha-synuclein is concentrated in presynaptic nerve terminals.

Engelender et al. (1999) identified a novel protein-interaction partner
of alpha-synuclein, which they designated synphilin-1, encoded by the
gene SNCAIP (603779). Synphilin-1 was present in many regions in brain,
including substantia nigra. They found that alpha-synuclein interacts in
vivo with synphilin-1 in neurons. Cotransfection of both proteins (but
not control proteins) in HEK293 cells yielded cytoplasmic eosinophilic
inclusions.

It has been shown that the ortholog of alpha-synuclein in the zebra
finch, synelfin, may play a role in song learning (George et al., 1995).

In a brief review article, Goedert (1997) noted that alpha-synuclein
contains 7 imperfect repeats of an 11-amino acid sequence, which may
mediate multimerization. The A53T mutation (163890.0001) associated with
familial Parkinson disease (PD; 168601) lies in a 9-amino acid segment
which connects the fourth and fifth such repeat. Goedert (1997)
speculated that alpha-synuclein may be a component of Lewy bodies, where
it may undergo abnormal aggregation. Spillantini et al. (1997) reported
that alpha-synuclein may be the major component of Lewy bodies
associated with Parkinson disease. Alpha-synuclein was found associated
with brainstem-type and cortical Lewy bodies in Parkinson disease and
Lewy body dementia (127750).

Aggregated alpha-synuclein proteins form brain lesions that are
hallmarks of neurodegenerative synucleinopathies, and oxidative stress
is implicated in the pathogenesis of some of these disorders. Giasson et
al. (2000) used antibodies to specific nitrated tyrosine residues in
alpha-synuclein to demonstrate extensive and widespread accumulation of
nitrated alpha-synuclein in the signature inclusions of Parkinson
disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer
disease, and multiple system atrophy (MSA; 146500) brains. The authors
also showed that nitrated alpha-synuclein is present in the major
filamentous building blocks of these inclusions, as well as in the
insoluble fractions of affected brain regions of synucleinopathies. The
selected and specific nitration of alpha-synuclein in these disorders
provides evidence to directly link oxidative and nitrative damage to the
onset and progression of neurodegenerative synucleinopathies.

Xu et al. (2002) demonstrated that accumulation of alpha-synuclein in
cultured human dopaminergic neurons results in apoptosis that requires
endogenous dopamine production and is mediated by reactive oxygen
species. In contrast, alpha-synuclein is not toxic in nondopaminergic
human cortical neurons, but rather exhibits neuroprotective activity.
Dopamine-dependent neurotoxicity is mediated by 54-83-kD soluble protein
complexes that contain alpha-synuclein and 14-3-3 protein (113508),
which are elevated selectively in the substantia nigra in Parkinson
disease. Thus, Xu et al. (2002) concluded that accumulation of soluble
alpha-synuclein protein complexes can render endogenous dopamine toxic,
suggesting a potential mechanism for the selectivity of neuronal loss in
Parkinson disease.

Da Costa et al. (2002) demonstrated that wildtype mammalian SNCA is
antiapoptotic when overexpressed in mouse neuronal cells. SNCA lowered
basal and staurosporin-induced caspase-3 immunoreactivity and activity,
and this was accompanied by a decrease in several other markers of
apoptosis. The antiapoptotic effect was reversed by 6-hydroxydopamine,
which triggered SNCA aggregation.

Lotharius and Brundin (2002) reviewed the literature on SNCA and
suggested a possible role for this protein in vesicle recycling via its
regulation of phospholipase D2 and its fatty acid-binding properties.
They hypothesized that impaired neurotransmitter storage arising from
SNCA mutations could lead to cytoplasmic accumulation of dopamine,
resulting in breakdown of this labile neurotransmitter in the cytoplasm
and promoting oxidative stress and metabolic dysfunction in the
substantia nigra.

Giasson et al. (2003) showed that alpha-synuclein induces fibrillization
of microtubule-associated protein tau (MAPT; 157140), and that
coincubation of alpha-synuclein and tau synergistically promotes
fibrillization of both proteins in vitro. In vivo studies of mice with
an alpha-synuclein mutation or a tau mutation showed filamentous
inclusions of both proteins, which are abundant neuronal proteins that
normally adopt an unfolded conformation but polymerize into amyloid
fibrils in disease. The findings suggested an interaction between
alpha-synuclein and tau that drives the formation of pathologic
inclusions in human neurodegenerative diseases.

Sharon et al. (2003) identified a cellular pool of highly soluble
oligomers of alpha-synuclein in cultured mesencephalic neurons, normal
mouse brain, and normal human brains. Exposure of cultured neurons to
polyunsaturated fatty acids increased alpha-synuclein oligomer levels,
whereas saturated fatty acids decreased them. Mice accumulated soluble
oligomers with age, and human brains from patients with PD or dementia
with Lewy bodies (DLB; 127750) had elevated amounts of the soluble,
lipid-dependent oligomers. Sharon et al. (2003) concluded that
alpha-synuclein interacts with polyunsaturated fatty acids in vivo to
promote the formation of soluble oligomers that precede the formation of
insoluble alpha-synuclein aggregates associated with neurodegenerative
disorders.

Outeiro and Lindquist (2003) observed that when expressed in yeast,
alpha-synuclein associated with the plasma membrane in a highly
selective manner, before forming cytoplasmic inclusions through a
concentration-dependent, nucleated process. Alpha-synuclein inhibited
phospholipase D, induced lipid droplet accumulation, and affected
vesicle trafficking. Outeiro and Lindquist (2003) concluded that their
readily manipulable system provided an opportunity to dissect the
molecular pathways underlying normal alpha-synuclein biology and the
pathogenic consequences of its misfolding.

Willingham et al. (2003) performed genomewide screens in yeast to
identify genes that enhance the toxicity of a mutant huntingtin fragment
or of alpha-synuclein. Of 4,850 haploid mutants containing deletions of
nonessential genes, 52 were identified that were sensitive to a mutant
huntingtin fragment, 86 that were sensitive to alpha-synuclein, and only
1 mutant that was sensitive to both. Genes that enhanced toxicity of the
mutant huntingtin fragment clustered in the functionally related
cellular processes of response to stress, protein folding, and
ubiquitin-dependent protein catabolism, whereas genes that modified
alpha-synuclein toxicity clustered in the processes of lipid metabolism
and vesicle-mediated transport. Genes with human orthologs were
overrepresented in their screens, suggesting that they may have
discovered conserved and nonoverlapping sets of cell-autonomous genes
and pathways that are relevant to Huntington disease (143100) and
Parkinson disease.

Iwata et al. (2003) found that the serine protease neurosin (KLK6;
602652) degraded alpha-synuclein and colocalized with pathologic
inclusions such as Lewy bodies and glial cytoplasmic inclusions. In cell
lysates, neurosin prevented alpha-synuclein polymerization by reducing
the amount of monomer and also by generating fragmented alpha-synucleins
that themselves inhibited the polymerization. Upon cellular stress,
neurosin was released from mitochondria to the cytosol, which resulted
in the increase of degraded alpha-synuclein species. Downregulation of
neurosin caused accumulation of alpha-synuclein within cultured cells.
The authors concluded that neurosin may play a significant role in
physiologic alpha-synuclein degradation and also in the pathogenesis of
synucleinopathies.

Cuervo et al. (2004) found that wildtype alpha-synuclein is selectively
translocated into lysosomes for degradation by the chaperone-mediated
autophagy pathway. The pathogenic A53T (163890.0001) and A30P
(163890.0002) alpha-synuclein mutants bound to LAMP2A (309060), the
receptor for this pathway, but appeared to act as uptake blockers
inhibiting both their own degradation and that of other substrates.
Cuervo et al. (2004) suggested that these findings may underlie the
toxic gain of function by the alpha-synuclein mutants.

Martinez et al. (2003) used a photocross-linking approach to show that
alpha-synuclein binds to calmodulin (114180) in bovine brain cells.
Further analysis showed that the binding occurred in a calcium-dependent
manner with the mutant A53T protein as well as with the wildtype
protein, and that calmodulin accelerated the formation of synuclein
fibrils in vitro.

Using several related experiments, Liu et al. (2004) demonstrated that
alpha-synuclein was associated with potentiation of synaptic
transmission in cultured rodent hippocampal cells. Application of
glutamate increased alpha-synuclein immunoreactivity and functional
bouton number in the presynaptic terminal. Glutamate and tetanic
application also resulted in increased spontaneous and evoked
postsynaptic currents, but these effects were not seen in cultured
hippocampal cells from Snca-null mice. Presynaptic injection of
alpha-synuclein increased neurotransmitter release via production of
nitric oxide. Liu et al. (2004) concluded that alpha-synuclein is
involved in synaptic plasticity by augmenting transmitter release from
the presynaptic terminal.

Cooper et al. (2006) found that the earliest defect following
alpha-synuclein expression in yeast was a block in endoplasmic
reticulum-to-Golgi vesicular trafficking. In a genomewide screen, the
largest class of toxicity modifiers were proteins functioning at this
same step, including the Rab guanosine triphosphate Ypt1p, which
associated with cytoplasmic alpha-synuclein inclusions. Elevated
expression of Rab1 (179508), the mammalian Ypt1 homolog, protected
against alpha-synuclein-induced dopaminergic neuron loss in animal
models of Parkinson disease. Thus, Cooper et al. (2006) concluded that
synucleinopathies may result from disruptions in basic cellular
functions that interface with the unique biology of particular neurons
to make them especially vulnerable.

Using mass spectrometry analysis and immunohistochemistry, Fujiwara et
al. (2002) showed that the ser129 residue of alpha-synuclein is
selectively and extensively phosphorylated in synucleinopathy lesions.
In vitro, phosphorylation at ser129 promoted insoluble fibril formation
that likely contributes to the pathogenesis of neurodegenerative
disorders.

Using detailed biochemical studies, Anderson et al. (2006) found that
the predominant form of alpha-synuclein within Lewy bodies isolated from
brains of patients with Lewy body dementia, multiple system atrophy, and
PARK1 was phosphorylated at ser129. A much smaller amount of
ser129-phosphorylated alpha-synuclein was found in the soluble fraction
of both control and diseased brains, suggesting that
ser129-phosphorylated alpha-synuclein shifts from the cytosol to be
deposited in Lewy bodies, and that phosphorylation enhances inclusion
formation. Other unusual biochemical characteristics of alpha-synuclein
in Lewy bodies included ubiquitination and the presence of several
C-terminally truncated alpha-synuclein species.

Outeiro et al. (2007) identified a potent inhibitor of sirtuin-2 (SIRT2;
604480) and found that inhibition of SIRT2 rescued alpha-synuclein
toxicity and modified inclusion morphology in a cellular model of
Parkinson disease. Genetic inhibition of SIRT2 via small interfering RNA
similarly rescued alpha-synuclein toxicity. The inhibitors protected
against dopaminergic cell death both in vitro and in a Drosophila model
of PD. Outeiro et al. (2007) concluded that their results suggest a link
between neurodegeneration and aging.

Beyer et al. (2008) demonstrated overexpression of SNCA112 in brains of
patients with Lewy body dementia. SNCA98 expression was increased in
brains from patients with DLB, Parkinson disease, and Alzheimer disease
compared to controls. Beyer et al. (2008) postulated that differentially
spliced SNCA isoforms may have different aggregation properties, which
may be important in neurodegeneration.

The RING-type E3 ubiquitin ligase SIAH1 (602212) is present in Lewy
bodies of the substantia nigra of Parkinson disease patients (Liani et
al., 2004). Using immunofluorescence analysis, Lee et al. (2008) found
that endogenous Siah1 and alpha-synuclein partially colocalized in cell
bodies and neuritic processes of rat PC12 cells and mouse cortical
neurons. Pull-down assays and coimmunoprecipitation analysis showed that
rat Siah1 and alpha-synuclein interacted in vitro and in vivo. Using
transfected HeLa cells, Lee et al. (2008) found that rat Siah1 bound the
human brain-enriched E2 ubiquitin-conjugating enzyme UBCH8 (UBE2L6;
603890) and facilitated mono- and diubiquitination of alpha-synuclein in
vivo. Ubiquitination of alpha-synuclein by Siah1 was disrupted by the
A30P mutation of alpha-synuclein, but not by the A53T mutation. Studies
in transfected HeLa and PC12 cells showed that Siah1-mediated
ubiquitination did not target alpha-synuclein for proteasomal
degradation, but rather promoted alpha-synuclein aggregation and
enhanced its neurotoxicity.

Burre et al. (2010) showed that maintenance of continuous presynaptic
SNARE complex assembly requires a nonclassical chaperone activity
mediated by synucleins. Specifically, alpha-synuclein directly bound to
the SNARE protein synaptobrevin-2/vesicle-associated membrane protein-2
(VAMP2; 185881) and promoted SNARE complex assembly. Moreover,
triple-knockout mice lacking synucleins developed age-dependent
neurologic impairments, exhibited decreased SNARE complex assembly, and
died prematurely. Thus, Burre et al. (2010) concluded that synucleins
may function to sustain normal SNARE complex assembly in a presynaptic
terminal during aging.

Bartels et al. (2011) reported that endogenous alpha-synuclein isolated
and analyzed under nondenaturing conditions from neuronal and
nonneuronal cell lines, brain tissue, and living human cells occurs in
large part as a folded tetramer of about 58 kD. Several methods,
including analytical ultracentrifugation, scanning transmission electron
microscopy, and in vitro cell crosslinking confirmed the occurrence of
the tetramer. Native cell-derived alpha-synuclein showed alpha-helical
structure without lipid addition and had much greater lipid-binding
capacity than the recombinant alpha-synuclein studied theretofore.
Whereas recombinantly expressed monomers aggregated into amyloid-like
fibrils in vitro, native human tetramers readily underwent little or no
amyloid-like aggregation. On the basis of their findings, Bartels et al.
(2011) proposed that destabilization of the helically folded tetramer
precedes alpha-synuclein misfolding and aggregation in Parkinson disease
and other human synucleinopathies, and that small molecules that
stabilize the physiologic tetramer could reduce alpha-synuclein
pathogenicity.

Nakamura et al. (2011) found that overexpression of wildtype human SNCA,
but not other synucleins, in HeLa cells and other cell lines caused
mitochondrial fragmentation. SNCA overexpression also caused a mild
disruption of Golgi, but had no effect on other organelles. Disruption
of mitochondria in COS cells was followed by loss of mitochondrial
membrane potential, formation of reactive oxygen species, disrupted
oxygen consumption and respiration, and apoptotic cell death. Similar
changes were observed in transgenic mice and cultured hippocampal
neurons expressing human SNCA. Mitochondrial fragmentation required
association of SNCA with mitochondrial membranes and depended upon SNCA
N-terminal threonines. Incubation with artificial membranes showed that
SNCA specifically interacted with the acidic phospholipid cardiolipin,
which is enriched in mitochondria, and reduced the size of membranes
containing cardiolipin. The SNCA mutants A53T and glu46 to lys (E46K;
163890.0004) bound mitochondrial membranes and caused mitochondrial
fragmentation upon overexpression, whereas the A30P SNCA mutant did not
bind mitochondrial membranes and did not cause mitochondria
fragmentation.

Loss-of-function mutations in the gene encoding the lysosomal enzyme
glucocerebrosidase (GCase, or GBA; 606463) lead to lysosomal
accumulation of its substrate, glucosylceramide (GlcCer), and result in
different forms of Gaucher disease (GD; see 230800), some of which
include features of PD. Mazzulli et al. (2011) found that postmortem
brains of patients with GD and features of PD, as well as mouse models
of GD, showed neuronal accumulation of SNCA. Functional loss of GCase
and resultant GlcCer accumulation in cultured mouse cortical neurons and
human neurons reprogrammed from induced pluripotent stem cells resulted
in compromised lysosomal degradation of long-lived proteins, including
SNCA. Elevated cellular GlcCer also promoted SNCA aggregation. SNCA
accumulation in turn inhibited normal lysosomal GCase activity in
neurons and PD brain. In apparently normal human cortical samples, SNCA
protein content, particularly high molecular mass species, correlated
inversely with GCase activity. Mazzulli et al. (2011) hypothesized that
a positive-feedback loop between defective SNCA and/or GCase could lead
to self-propagating neurodegeneration over time.

Luk et al. (2012) found that in wildtype nontransgenic mice, a single
intrastriatal inoculation of synthetic alpha-synuclein fibrils led to
the cell-to-cell transmission of pathologic alpha-synuclein and
Parkinson-like Lewy pathology in anatomically interconnected regions.
Lewy pathology accumulation resulted in progressive loss of dopamine
neurons in the substantia nigra pars compacta, but not in the adjacent
ventral tegmental area, and was accompanied by reduced dopamine levels
culminating in motor deficits. This recapitulation of a
neurodegenerative cascade thus established a mechanistic link between
transmission of pathologic alpha-synuclein and the cardinal features of
Parkinson disease.

- Interaction With Parkin

Shimura et al. (2001) hypothesized that alpha-synuclein and parkin
(602544) interact functionally, namely, that parkin ubiquitinates
alpha-synuclein normally and that this process is altered in autosomal
recessive Parkinson disease (600116). Shimura et al. (2001) identified a
protein complex in normal human brain that includes parkin as the E3
ubiquitin ligase, UBCH7 (603721) as its associated E2
ubiquitin-conjugating enzyme, and a novel 22-kD glycosylated form of
alpha-synuclein (alpha-Sp22) as its substrate. In contrast to normal
parkin, mutant parkin associated with autosomal recessive Parkinson
disease failed to bind alpha-Sp22. In an in vitro ubiquitination assay,
alpha-Sp22 was modified by normal, but not mutant, parkin into
polyubiquitinated, high molecular weight species. Accordingly,
alpha-Sp22 accumulated in a nonubiquitinated form in parkin-deficient
Parkinson disease brains. Shimura et al. (2001) concluded that
alpha-Sp22 is a substrate for parkin's ubiquitin ligase activity in
normal human brain and that loss of parkin function causes pathologic
accumulation of alpha-Sp22. These findings demonstrated a critical
biochemical reaction between the 2 Parkinson disease-linked gene
products and suggested that this reaction underlies the accumulation of
ubiquitinated alpha-synuclein in conventional Parkinson disease.

Chung et al. (2001) showed that parkin interacts with and ubiquitinates
the alpha-synuclein-interacting protein synphilin-1 (603779).
Coexpression of alpha-synuclein, synphilin-1, and parkin resulted in the
formation of Lewy body-like ubiquitin-positive cytosolic inclusions.
They further showed that familial mutations in parkin disrupt the
ubiquitination of synphilin-1 and the formation of the
ubiquitin-positive inclusions. Chung et al. (2001) concluded that their
results provided a molecular basis for the ubiquitination of Lewy
body-associated proteins and linked parkin and alpha-synuclein in a
common pathogenic mechanism through their interaction with synphilin-1.

Petrucelli et al. (2002) found that overexpression of mutant
alpha-synuclein in human neuroblastoma cells resulted in impaired
proteasome activity, resulting in decreased cell viability. Mutant
alpha-synuclein was selectively toxic to tyrosine hydroxylase (TH;
191290)-positive neurons from the mouse midbrain, but not to TH-negative
midbrain neurons or hippocampal neurons. Wildtype parkin was able to
rescue the toxic effect of proteasome inhibition or mutant
alpha-synuclein, but mutant parkin was not protective. The findings
showed that both the parkin and SNCA genes alter the ability of neurons
to tolerate reduced proteasome activity, indicating a common pathway in
selective neurodegeneration in PD.

In neuroblastoma cells, Kawahara et al. (2008) found that in the
presence of proteasomal inhibition, SNCA promoted the accumulation of
insoluble parkin as well as insoluble alpha-tubulin (see, e.g., TUBA1A,
602529). Immunoblot analysis of brain samples from patients with Lewy
body dementia showed increased levels of insoluble parkin and
alpha-tubulin. Coimmunoprecipitation studies indicated that parkin and
SNCA colocalized, particularly in the presence of a proteasomal
inhibitor. Overexpression of SNCA resulted in decreased parkin and
alpha-tubulin ubiquitination, accumulation of insoluble parkin, and
cytoskeletal alterations with reduced neurite outgrowth. The findings
suggested that accumulation of alpha-synuclein might contribute to the
pathogenesis of PD and other Lewy body diseases by promoting alterations
in parkin and tubulin solubility, which, in turn, might compromise
neural function by damaging the neuronal cytoskeleton.

MOLECULAR GENETICS

- Parkinson Disease and Lewy Body Dementia

Polymeropoulos et al. (1996) demonstrated that the Parkinson disease
phenotype in a large family of Italian descent could be mapped to
4q21-q23. Designated Parkinson disease type 1 (PARK1; 168601), the
disorder in this family was well documented to be typical for Parkinson
disease, including Lewy bodies, with the exception of a relatively early
age of onset of illness at 46 +/- 13 years. In this family, the
penetrance of the gene was estimated to be 85%. Since the SNCA gene maps
to the same region, it was considered an excellent candidate for the
site of the mutation in PARK1. In the Italian family, Polymeropoulos et
al. (1997) found a G-to-A transition in nucleotide 209 of the SNCA gene,
which resulted in an ala53-to-thr substitution (A53T; 163890.0001). The
same A53T mutation segregated with the Parkinson disease phenotype in 3
Greek kindreds. In these families also, the onset of the disease
occurred relatively early.

Heintz and Zoghbi (1997) suggested that alpha-synuclein may provide a
link between Parkinson disease and Alzheimer disease (104300), and
possibly other neurodegenerative diseases.

Farrer et al. (1998) did not find mutations in the SNCA gene in 6
familial cases of autosomal dominant PD or 2 cases of amyotrophic
lateral sclerosis-parkinsonism/dementia complex of Guam (105500). Scott
et al. (1997) excluded linkage to alpha-synuclein in 94 multiplex (at
least 2 sampled affecteds with Parkinson disease) families.

Scott et al. (1999) screened the translated exons of the SNCA gene for
the A53T mutation in 356 affected individuals from 186 multiplex
families with Parkinson disease. One Greek American family segregated
this mutation as an autosomal dominant trait, giving a frequency for
this mutation of 1 in 186, or 0.5%. The phenotype in this family was
consistent with the other Greek and Italian families reported with this
mutation. Other than autosomal dominant inheritance and wider
intrafamilial variation in age at onset, there were no significant
differences in the phenotype in this family and the other families in
the data set. Members of the family remaining in Greece had been
reported by Markopoulou et al. (1995). Scott et al. (1999) concluded
that the SNCA gene is not a major risk factor in familial Parkinson
disease.

In affected members of a Spanish family with autosomal dominant Lewy
body dementia and parkinsonism (DLB; 127750), Zarranz et al. (2004)
identified a point mutation in the SNCA gene (163890.0004).

Pals et al. (2004) reported evidence suggesting that SNCA promoter
variability may contribute to susceptibility to PD. Among 175 Belgian PD
patients, there was overrepresentation of minimum promoter haplotypes
spanning approximately 15.3 kb. Specifically, the C-261-A-G-A-C and
T-263-G-A-C-G haplotypes were found in 29% and 9% of patients compared
to 20% and 3% of controls, respectively. The haplotypes encompassed the
Rep1 promoter region but did not rely on Rep1 genotypes.

Alleles at NACP-Rep1, the polymorphic microsatellite repeat located
approximately 10 kb upstream of the SNCA gene, were found to be
associated with differing risks of sporadic Parkinson disease.
Chiba-Falek and Nussbaum (2001) and Chiba-Falek et al. (2003) found that
NACP-Rep1 acts as a negative modulator of SNCA transcription with an
effect that varied 3-fold among different NACP-Rep1 alleles. Given that
duplications and triplications of SNCA have been implicated in familial
Parkinson disease, even a 1.5- to 2-fold increase in SNCA expression
may, over many decades, contribute to PD. Chiba-Falek et al. (2005)
identified factors that bind to NACP-Rep1 and potentially contribute to
SNCA transcriptional modulation by pulling down proteins that bind to
NACP-Rep1 and identifying them by mass spectrometry. One of the proteins
was PARP1 (173870), a DNA-binding protein and transcriptional regulator.
PARP1 binding to NACP-Rep1 specifically reduced the transcriptional
activity of the SNCA promoter/enhancer in luciferase reporter assays.
The association of different NACP-Rep1 alleles with Parkinson disease
may be mediated, in part, by the effect of PARP1, as well as other
factors, on SNCA expression.

Mueller et al. (2005) found no association between the SNCA promoter
region, including the sequence repeat Rep1, and the development of PD
among 669 German sporadic PD patients.

In a study of 557 PD patient-control pairs, Mamah et al. (2005) found
that individuals with the SNCA Rep1 261/261 or MAPT H1/H1 genotypes had
an increased risk of PD compared to those with neither genotype (odds
ratio of 1.96); however, the combined effect of the 2 genotypes was the
same as for either genotype alone. Mamah et al. (2005) suggested that
the MAPT H1/H1 genotype may cause increased SNCA fibrillization in
persons with lower SNCA protein concentrations due to genotypes other
than Rep1 261/261. In persons with the Rep1 261/261 genotype, the MAPT
H1/H1 genotype confers no additional risk because the SNCA protein is
already at threshold concentration for self-fibrillization.

In a large study involving 2,692 PD patients from 11 different sites,
Maraganore et al. (2006) found that the 263-bp Rep1 allele was
associated with an increased risk of Parkinson disease (odds ratio of
1.43). The 259-bp Rep1 allele was associated with a reduced risk of PD
(OR of 0.86). Genotypes defined by Rep1 alleles did not influence age at
disease onset.

Among 659 PD patients, Goris et al. (2007) found a synergistic
interaction between the MAPT H1 haplotype and an A-to-G SNP (dbSNP
rs356219) in the 3-prime region of the SNCA gene. Carrying the
combination of risk genotypes at both loci approximately doubled the
risk of disease (p = 3 x 10(-6)). The findings suggested that MAPT and
SNCA are involved in shared or converging pathogenic pathways and may
have a synergistic effect. Cognitive decline and the development of
dementia was associated with the H1/H1 genotype (p = 10(-4)). In a final
analysis that combined data from other studies, Goris et al. (2007)
confirmed the association of the H1/H1 genotype with PD (odds ratio of
1.4; p = 2 x 10(-19)).

In a statistical analysis of 5,302 PD patients and 4,161 controls from
15 sites, Elbaz et al. (2011) found no evidence for an interactive
effect between the H1 haplotype in the MAPT gene and SNPs in the SNCA
gene on disease. Variation in each gene was associated with PD risk,
indicating independent effects.

- Multiple System Atrophy

See 146500 for a discussion of a possible association between variation
in the SNCA gene and multiple system atrophy (MSA).

- SNCA Gene Duplication/Triplication

In affected members of 3 unrelated families, 2 French and 1 Italian,
with classic autosomal dominant Parkinson disease, Ibanez et al. (2004)
and Chartier-Harlin et al. (2004) identified heterozygosity for
whole-gene duplication of the SNCA gene (163890.0005).

In a large family with parkinsonism (PARK4; 605543) reported by Waters
and Miller (1994), Singleton et al. (2003) found evidence consistent
with triplication of the SNCA gene (163890.0003). The triplicated region
contains an estimated 17 genes, including SNCA. Johnson et al. (2004)
did not find SNCA multiplications in 101 familial PD probands, 325
sporadic PD cases, 65 patients with dementia with Lewy bodies, or 366
healthy controls, and concluded it is a rare cause of disease. The
patient cohort was white and Hispanic.

Ross et al. (2008) reviewed the clinical features and breakpoints
involved in 5 previously reported families with either SNCA duplication
(Chartier-Harlin et al., 2004, Fuchs et al., 2007, Nishioka et al.,
2006) or SNCA triplication (Singleton et al., 2003, Farrer et al.,
2004). The multiplications ranged in size from 0.4 Mb to 4.93-4.97 Mb,
the latter of which encompassed 31 different gene transcripts.
Microsatellite analysis indicated that SNCA genomic duplication resulted
from intraallelic (segmental duplication) or interallelic recombination
with unequal crossing over, whereas both mechanisms appeared to be
required for genomic SNCA triplication. Although no single repeat was
consistently observed at the breakpoints, a variety of Alu and LINE
repeats were found at the breakpoints. A comparison of the phenotypes
indicated that dosage of the SNCA gene, and not other genes in the
region, specifically contribute to the variability in clinical
observations among families, which ranged from classic Parkinson disease
to Lewy body dementia with autonomic features. Increased SNCA gene
dosage was associated with a more severe phenotype.

Ibanez et al. (2009) identified duplications of the SNCA gene in 4
(1.5%) of 264 mostly European families with typical PD. One (4.5%) of 22
families with atypical PD (PARK4), including rapid progression and
severe cognitive impairment, was found to have triplication of the SNCA
gene. Genotyping and dosage analysis indicated that SNCA multiplications
occurred independently. There was a correlation between disease severity
and SNCA copy number. The largest duplication was 4.50-5.29 Mb and
included 33 to 34 genes, although the severity in this family did not
differ from the other families. Ibanez et al. (2009) concluded that
alterations in SNCA gene dosage due to rearrangements may be more common
than point mutations.

- Studies on Mutant Alpha-Synuclein Protein

Narhi et al. (1999) presented evidence related to the pathogenic
mechanism of Parkinson disease caused by the 2 known mutants, ala30 to
pro (A30P; 163890.0002) and A53T. They showed that both wildtype and
mutant alpha-synuclein form insoluble fibrillar aggregates with
antiparallel beta-sheet structure upon incubation at physiologic
temperature in vitro. Importantly, aggregate formation was accelerated
by both Parkinson disease-linked mutations. Under the experimental
conditions, the lag time for the formation of precipitable aggregates
was about 280 hours for the wildtype protein, 180 hours for the A30P
mutant protein, and only 100 hours for the A53T mutant protein. These
data suggested that the formation of alpha-synuclein aggregates could be
a critical step in the pathogenesis of Parkinson disease, which is
accelerated by the Parkinson disease-linked mutations.

Tabrizi et al. (2000) generated stable, inducible cell models expressing
wildtype or Parkinson disease-associated mutant (209G-A; 163890.0001)
alpha-synuclein in human-derived HEK293 cells. Increased expression of
either wildtype or mutant alpha-synuclein resulted in the formation of
cytoplasmic aggregates which were associated with the vesicular
(including monoaminergic) compartment. Expression of mutant
alpha-synuclein induced a significant increase in sensitivity to
dopamine toxicity compared with wildtype protein expression.

In an in vitro study, Conway et al. (2000) compared the rates of
disappearance of monomeric alpha-synuclein and appearance of fibrillar
alpha-synuclein for the wildtype and 2 mutant proteins, A53T and A30P,
as well as equimolar mixtures that may model heterozygous Parkinson
disease patients. Whereas A53T and an equimolar mixture of A53T and
wildtype fibrillized more rapidly than wildtype alpha-synuclein, the
A30P mutation and its corresponding equimolar mixture with wildtype
fibrillized more slowly. However, under conditions that ultimately
produced fibrils, the A30P monomer was consumed at a comparable rate or
slightly more rapidly than the wildtype monomer, whereas A53T was
consumed even more rapidly. The difference between these trends
suggested the existence of nonfibrillar alpha-synuclein oligomers, some
of which were separated from fibrillar and monomeric alpha-synuclein by
sedimentation followed by gel-filtration chromatography. Conway et al.
(2000) concluded that drug candidates that inhibit alpha-synuclein
fibrillization but do not block its oligomerization could mimic the A30P
mutation and may therefore accelerate disease progression.

Tanaka et al. (2001) created PC12 cell lines expressing mutant
alpha-synuclein with the ala30-to-pro substitution (A30P; 163890.0002).
These cells showed decreased proteasomal activity without direct
toxicity and increased sensitivity to apoptotic cell death when treated
with subtoxic concentrations of an exogenous proteasome inhibitor.
Apoptosis was accompanied by mitochondrial depolarization and elevation
of caspase-3 (600636) and caspase-9 (602234) and was blocked by
cyclosporin A. The authors suggested that expression of mutant
alpha-synuclein results in sensitivity to impairment of proteasome
activity, leading to mitochondrial abnormalities and neuronal cell
death.

Lashuel et al. (2002) demonstrated that mutant amyloid proteins
associated with familial Alzheimer and Parkinson diseases formed
morphologically indistinguishable annular protofibrils that resemble a
class of pore-forming bacterial toxins, suggesting that inappropriate
membrane permeabilization might be the cause of cell dysfunction and
even cell death in amyloid diseases. The A30P (163890.0002) and A53T
(163890.0001) alpha-synuclein mutations associated with Parkinson
disease both promote protofibril formation in vitro relative to wildtype
alpha-synuclein. Lashuel et al. (2002) examined the structural
properties of A30P, A53T, and amyloid beta 'Arctic' (104760.0013)
protofibrils for shared structural features that might be related to
their toxicity. The protofibrils contained beta-sheet-rich oligomers
comprising 20 to 25 alpha-synuclein molecules, which formed amyloid
protofibrils with a pore-like morphology.

Mature alpha-synuclein is a small 14-kD protein with a central core
region (residues 61-95) containing hydrophobic amino acids, known as the
NAC region, that is responsible for fibril formation. Under physiologic
conditions, alpha-synuclein is an unfolded protein with little or no
ordered structure. Sode et al. (2005) found that a variant protein
constructed with 2 hydrophilic residues replacing hydrophilic residues
(val70thr/val71thr) retained the stable unfolded status better than the
wildtype protein, and also prevented fibril formation when mixed with
the wildtype protein or the mutant A53T protein.

Wildtype alpha-synuclein adopts several conformations that shield the
amyloidogenic core region of the protein through long-range interactions
between the N- and C- termini of the protein. Using nuclear magnetic
resonance (NMR) spectroscopy to evaluate structural features, Bertoncini
et al. (2005) found that mutant A53T and A30P alpha-synuclein proteins
caused structural fluctuations that lost the native conformations and
disrupted the autoinhibitory long-range interactions. The findings
suggested that the mutations may foster self-association and fibril
formation, resulting in a toxic gain of function.

Smith et al. (2005) generated A53T (163890.0001) mutant
alpha-synuclein-inducible PC12 cell lines using the Tet-off regulatory
system. Inducing expression of A53T alpha-synuclein in differentiated
PC12 cells decreased proteasome activity, increased the intracellular
reactive oxygen species (ROS) level, and caused up to 40% cell death,
which was accompanied by mitochondrial cytochrome C release and
elevation of caspase-9 and -3 activities. Cell death was partially
blocked by cyclosporine A (an inhibitor of the mitochondrial
permeability transition process), z-VAD (a pan-caspase inhibitor), and
inhibitors of caspase-9 and -3. Furthermore, induction of A53T
alpha-synuclein increased endoplasmic reticulum (ER) stress and elevated
caspase-12 (608633) activity. The authors concluded that both ER stress
and mitochondrial dysfunction may contribute to A53T
alpha-synuclein-induced cell death.

Using optical imaging with a pH-sensitive marker, Nemani et al. (2010)
found that overexpression of SNCA inhibited synaptic vesicle exocytosis
in cultured hippocampal neurons and in hippocampal slices from
transgenic mice that overexpressed the SNCA gene. These transgenic mouse
brains did not show SNCA-immunoreactive aggregates. The mechanism of
decreased neurotransmitter release was determined to be a specific
reduction in the size of the synaptic vesicle recycling pool.
Ultrastructural analysis showed reduced synaptic vesicle density at the
active zone, and imaging further revealed a defect in the reclustering
of synaptic vesicles after endocytosis.

- Alcohol Dependence

Bonsch et al. (2005) found an association between the length of the SNCA
REP1 allele and alcohol dependence in 135 Caucasian alcoholic patients
and 101 healthy Caucasian controls. The longer 273- and 271-bp alleles
were more frequent in alcoholic patients compared to controls (p less
than 0.001), and SNCA mRNA expression levels were correlated with the
longer SNCA REP1 alleles.

ANIMAL MODEL

Abeliovich et al. (2000) developed mice homozygously deleted for
alpha-synuclein by targeted disruption. Alpha-synuclein -/- mice were
viable and fertile; they exhibited intact brain architecture and
possessed a normal complement of dopaminergic cell bodies, fibers, and
synapses. Nigrostriatal terminals of alpha-synuclein -/- mice displayed
a standard pattern of dopamine discharge and reuptake in response to
simple electrical stimulation. However, they exhibited an increased
release with paired stimuli that could be mimicked by elevated calcium.
Concurrent with the altered dopamine release, alpha-synuclein -/- mice
displayed a reduction in striatal dopamine and an attenuation of
dopamine-dependent locomotor response to amphetamine. These findings
supported the hypothesis that alpha-synuclein is an essential
presynaptic, activity-dependent negative regulator of dopamine
neurotransmission.

Masliah et al. (2000) developed transgenic mice that expressed wildtype
alpha-synuclein under the control of the promoter of the
platelet-derived growth factor-beta gene (190040), which is expressed in
all neurons. Neuronal expression of human alpha-synuclein resulted in
progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive
inclusions in neurons in the neocortex, hippocampus, and substantia
nigra. Ultrastructural analysis revealed both electron-dense
intranuclear deposits and cytoplasmic inclusions. These alterations were
associated with loss of dopaminergic terminals in the basal ganglia and
with motor impairments. Masliah et al. (2000) concluded that
accumulation of wildtype alpha-synuclein may play a causal role in
Parkinson disease and related conditions.

Feany and Bender (2000) produced transgenic fly lines that produced
normal human alpha-synuclein and separate lines with each of the 2
mutant proteins linked to familial Parkinson disease, A30P (163890.0002)
and A53T (163890.0001) alpha-synuclein. Pan-neural expression of human
alpha-synuclein resulted in adult-onset loss of dopaminergic neurons,
filamentous intraneuronal inclusions containing alpha-synuclein
reminiscent of Lewy bodies, and locomotor dysfunction. Drosophila
expressing the A30P alpha-synuclein lost their climbing ability earlier
than flies expressing wildtype or A53T alpha-synuclein. However, all
transgenic flies showed premature loss of climbing ability. In addition
to degenerative changes in the brain, retinal degeneration also occurred
when alpha-synuclein was expressed specifically in the eye. Expression
of wildtype or mutant alpha-synuclein during development of the eye
produced no effect. However, continued expression of alpha-synuclein in
the adult produced retinal degeneration that was detectable by 10 days
and marked at 30 days in transgenic flies expressing wildtype, A30P, or
A53T alpha-synuclein.

Auluck et al. (2002) investigated whether HSP70 (140550) could mitigate
dopaminergic neuron loss induced by alpha-synuclein in flies with
mutated alpha-synuclein. They used a transgenic line encoding human
HSP70 to coexpress HSP70 with alpha-synuclein. Upon coexpression of
HSP70, Auluck et al. (2002) found complete maintenance of normal numbers
of dopaminergic neurons in aged flies. Although alpha-synuclein
expression in the absence of HSP70 resulted in a 50% loss of these
neurons in dorsomedial clusters by 20 days, in the presence of added
HSP70, the same number of dopaminergic neurons were present at 20 days
as were present at 1 day. Protection was specific to HSP70.

Some patients have clinical and pathologic features of Alzheimer disease
and Parkinson disease, raising the possibility of overlapping
pathogenetic pathways. Masliah et al. (2001) generated transgenic mice
with neuronal expression of human beta-amyloid peptides,
alpha-synuclein, or both. The functional and morphologic alterations in
doubly transgenic mice resembled the Lewy body variant of Alzheimer
disease (127750). These mice had severe deficits in learning and memory,
developed motor deficits earlier than the alpha-synuclein singly
transgenic mice, and showed prominent age-dependent degeneration of
cholinergic neurons and presynaptic terminals. They also had more
alpha-synuclein-immunoreactive neuronal inclusions than alpha-synuclein
singly transgenic mice. Ultrastructurally, some of these inclusions were
fibrillar in doubly transgenic mice, whereas all inclusions were
amorphous in alpha-synuclein singly transgenic mice. Beta-amyloid
peptides promoted aggregation of alpha-synuclein in a cell-free system
and intraneuronal accumulation of alpha-synuclein in cell culture.
Beta-amyloid peptides may contribute to the development of Lewy body
diseases by promoting the aggregation of alpha-synuclein and
exacerbating alpha-synuclein-dependent neuronal pathologic changes.
Therefore, treatments that block the production of beta-amyloid peptides
could benefit a broader spectrum of disorders than previously
anticipated.

To better understand the pathogenic relationship between alterations in
the biology of alpha-synuclein and PD-associated neurodegeneration, Lee
et al. (2002) generated multiple lines of transgenic mice expressing the
human SNCA mutations A30P or A53T. The mice expressing the A53T human
alpha-synuclein, but not wildtype or the A30P variant, developed
adult-onset neurodegenerative disease with a progressive motoric
dysfunction leading to death. Pathologically, affected mice exhibited
neuronal abnormalities (in perikarya and neurites) including pathologic
accumulations of alpha-synuclein and ubiquitin.
Alpha-synuclein-dependent neurodegeneration was associated with abnormal
accumulation of detergent-insoluble alpha-synuclein.

Ihara et al. (2007) found that deletion of Sept4 (603696) in transgenic
mice expressing human alpha-synuclein with the PD-associated A53T
mutation exacerbated PD-like symptoms, including elevated amyloid
deposits containing pathologically phosphorylated alpha-synuclein and
more severe loss of motor neurons and astrocyte gliosis. In vitro
studies showed that Sept4 interacted directly with alpha-synuclein,
suppressed self-aggregation of mutant alpha-synuclein, and partially
interfered with pathologic phosphorylation of mutant alpha-synuclein.
Ihara et al. (2007) concluded that SEPT4 may prevent alpha-synuclein
self-aggregation or shield alpha-synuclein from serine phosphorylation
in PD.

MPTP, a neurotoxin that inhibits mitochondrial complex I (see 252010),
is a prototype for an environmental cause of PD because it produces a
pattern of neurodegeneration of dopamine neurons that closely resembles
the neuropathology of PD. Dauer et al. (2002) showed that
alpha-synuclein-null mice displayed striking resistance to MPTP-induced
degeneration of dopamine neurons and dopamine release; this resistance
appeared to result from an inability of the toxin to inhibit complex I.
Contrary to predictions from in vitro data, this resistance was not due
to abnormalities of the dopamine transporter, which appeared to function
normally in the null mice. The results suggested that some genetic and
environmental factors that increase susceptibility to PD may interact
with a common molecular pathway, and demonstrated that normal
alpha-synuclein function may be important to dopamine neuron viability.

Junn et al. (2003) demonstrated that tissue transglutaminase (190196)
catalyzes the formation of alpha-synuclein aggregates in vitro and also
in cellular models. Furthermore, they showed the presence of
epsilon(gamma-glutamyl)-lysine bonds, which is indicative of
transglutaminase activity, in Parkinson disease with Lewy bodies
(605543) and in dementia with Lewy bodies (127750). The findings
suggested that this enzyme is involved in the formation of Lewy bodies
by crosslinking alpha-synuclein and possibly in the pathogenesis of
alpha-synucleinopathies.

To identify genes influencing alcohol consumption, Liang et al. (2003)
used QTL and gene expression analyses as complementary methods in a
study of inbred alcohol-preferring (iP) and alcohol-nonpreferring (iNP)
Wistar rat strains, showing highly discordant alcohol consumption
scores. A genome screen identified QTLs on chromosomes 3, 4, and 8. The
chromosome 4 QTL produced a lod score of 9.2 that accounted for 10% of
the phenotypic and approximately 30% of the genetic variation in alcohol
consumption. The gene expression analysis identified differential
expression of genes and 3-prime ESTs. Of the genes that were
differentially expressed in iP and iNP rats, SNCA was prioritized for
further investigation because it was located in a region of mouse
chromosome 6 syntenic to the rat chromosome 4 QTL, and it was shown to
modulate dopamine transmission, which was thought to be involved with
neurodegenerative and neuropsychiatric disorders such as alcoholism
(103780). Liang et al. (2003) found that alpha-synuclein was expressed
in the hippocampus at more than 2-fold higher levels in the iP than in
the iNP rats. In situ hybridization demonstrated that protein levels in
the hippocampus were also higher in iP rats. Higher protein levels were
also observed in the caudate putamen of iP rats compared with iNP rats.
Sequence analysis identified 2 SNPs in the 3-prime UTR of the SNCA cDNA.
One of the SNPs was used to map the gene, by using recombination-based
methods, to a region within the chromosome 4 QTL. A nucleotide exchange
in the iNP 3-prime UTR reduced expression of the luciferase reporter
gene in cultured neuroblastoma cells. These results suggested that
differential expression of the SNCA gene may contribute to alcohol
preference in the iP rats.

Transgenic Drosophila expressing human SNCA carrying the ala30-to-pro
(A30P; 163890.0002) mutation faithfully replicate essential features of
human Parkinson disease, including age-dependent loss of dopaminergic
neurons, Lewy body-like inclusions, and locomotor impairment. Scherzer
et al. (2003) characterized expression of the entire Drosophila genome
at presymptomatic, early, and advanced disease stages. Fifty-one
signature transcripts were tightly associated with A30P SNCA expression.
At the presymptomatic stage, expression changes revealed specific
pathology. In age-matched transgenic Drosophila carrying an
arg406-to-trp mutation in tau (157140.0003), the transcription of mutant
SNCA-associated genes was normal, suggesting highly distinct pathways of
neurodegeneration.

Chen and Feany (2005) found that aged Drosophila expressing wildtype
human SNCA developed dopaminergic neuron loss associated with SNCA
phosphorylated at ser129. The ser129-to-ala mutation, which is resistant
to phosphorylation, suppressed neuronal loss and increased insoluble
inclusion body formation. In contrast, ser129 to asp, which mimics
phosphorylation, resulted in increased neuronal SNCA toxicity. Chen and
Feany (2005) suggested that sequestration of alpha-synuclein into
insoluble inclusion bodies may protect cells from neurotoxicity. and
that ser129 is essential for the toxicity of SNCA in dopaminergic
neurons.

Mutations in the human ATP13A2 gene (610513) result in PARK9 (KRS;
606693). Gitler et al. (2009) showed that the yeast homolog of human
ATP13A2, termed Ypk9, could suppress overexpression-induced Snca
toxicity both in yeast and in cultured rat dopaminergic neurons by
decreasing intracellular Snca inclusions. Ypk9 knockdown in C. elegans
enhanced misfolding of Snca. In addition, Ypk9 was found to help protect
cells from manganese toxicity. These findings suggested a functional
connection between Snca and the PARK9 susceptibility locus, as well as
with manganese exposure as a possible environmental risk factor for PD.

Using recombinant adenovirus-associated vector (rAAV2/6)-mediated
expression of alpha-synuclein, da Silveira et al. (2009) developed a rat
model of PD in which there was a correlation between neurodegeneration
and formation of small filamentous alpha-synuclein aggregates.
Serine-129 has been shown to be the major phosphorylation site on
alpha-synuclein in PD patients (see Fujiwara et al., 2002 and Anderson
et al., 2006). Da Silveira et al. (2009) demonstrated that a mutation
preventing phosphorylation (ser129 to ala; S129A) significantly
increased alpha-synuclein toxicity and led to enhanced formation of
beta-sheet-rich, proteinase K-resistant aggregates, increased affinity
for intracellular membranes, a disarrayed network of neurofilaments, and
enhanced alpha-synuclein nuclear localization. The expression of a
mutation mimicking phosphorylation (ser129 to asp; S129D) did not lead
to dopaminergic cell loss. Nevertheless, fewer but larger aggregates
were formed, and signals of apoptosis were also activated in rats
expressing the phosphorylation-mimicking form of alpha-synuclein. Da
Silveira et al. (2009) suggested that phosphorylation does not play an
active role in the accumulation of cytotoxic preinclusion aggregates,
and that constitutive expression of phosphorylation-mimicking forms of
alpha-synuclein does not protect from neurodegeneration.

Cronin et al. (2009) reported the effects of 3 distinct SNCA-Rep1
variants in the brains of 72 mice transgenic for the entire human SNCA
locus. Human SNCA mRNA and protein levels were increased 1.7- and
1.25-fold, respectively, in homozygotes for the expanded, PD
risk-conferring allele compared with homozygotes for the shorter,
protective allele. When adjusting for the total SNCA protein
concentration (endogenous mouse and transgenic human) expressed in each
brain, the expanded risk allele contributed 2.6-fold more to the SNCA
steady-state than the shorter allele. Furthermore, targeted deletion of
Rep1 resulted in the lowest human SNCA mRNA and protein concentrations
in murine brain but no decrease was observed in blood lysates from the
same mice. Cronin et al. (2009) concluded that Rep1 regulates human SNCA
expression by enhancing its transcription in the adult nervous system,
and suggested that homozygosity for the expanded Rep1 allele may mimic
locus multiplication, thereby elevating PD risk.

Lin et al. (2009) found that overexpression of Lrrk2 (609007), either
wildtype or mutant, in transgenic mice carrying an A53T Snca mutation
(163890.0001) accelerated the PD-related neuropathologic abnormalities
by promoting aggregation and accumulation of cytotoxic Snca-containing
protein inclusions in cell bodies of striatal neurons. However, the 2
proteins did not appear to interact directly. Degenerating neurons
showed fragmentation of the Golgi apparatus, which correlated with the
accumulation of Snca. Immunostaining studies showed evidence of impaired
microtubule assembly within the cells as well as impairment of the
ubiquitin-proteasome system. Mitochondrial function was also impaired.
Inhibition of Lrrk2 in these mice suppressed these abnormalities and
delayed the progression of neuropathology in A53T mutant mice. The
findings suggested that Lrrk2 may regulate mutant Snca-mediated
neuropathology by modulating the intracellular trafficking and
microtubule-based axonal transport of Snca.

Ramsey et al. (2010) noted that several in vitro studies had suggested
that DJ1 (602533) could inhibit the formation and protect against the
effects of SNCA aggregation. They crossbred transgenic mice (M83)
expressing the human pathogenic SNCA A53T mutation (163890.0001) on a
DJ1-null background (M83-DJ-null mice) to determine the effects of the
lack of DJ1 in these mice. M83 and M83-DJ-null mice displayed a similar
onset of disease and pathologic changes, and none of the analyses to
assess for changes in pathogenesis revealed any significant differences
between M83 and M83-DJ-null mice. The authors suggested that DJ1 may not
function to modulate SNCA directly and does not appear to play a role in
protecting against the deleterious effects of A53T in vivo. Ramsey et
al. (2010) speculated that SNCA and DJ1 mutations may lead to Parkinson
disease via independent mechanisms.

Kuo et al. (2010) developed transgenic mice expressing mutant
alpha-synuclein, either A53T (163890.0001) or A30P (163890.0002), from
insertions of an entire human SNCA gene as models for the familial
disease. Both the A53T and A30P lines showed abnormalities in enteric
nervous system (ENS) function and synuclein-immunoreactive aggregates in
ENS ganglia by 3 months of age. The A53T line also had abnormal motor
behavior, but neither line demonstrated cardiac autonomic abnormalities,
olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body
inclusions, or neurodegeneration. These animals recapitulated the early
gastrointestinal abnormalities seen in human Parkinson disease.

Using a mouse prion protein promoter, Smith et al. (2010) generated
synphilin-1 transgenic mice, which did not display PD-like phenotypes.
However, synphilin-1/A53T alpha-synuclein double-transgenic mice
survived longer than A53T alpha-synuclein single-transgenic mice. There
were attenuated A53T alpha-synuclein-induced motor abnormalities and
decreased astroglial reaction and neuronal degeneration in brains in
double-transgenic mice. Overexpression of synphilin-1 decreased
caspase-3 (CASP3; 600636) activation, increased beclin-1 (BECN1; 604378)
and LC3 II (see 601242) expression, and promoted formation of
aggresome-like structures, suggesting that synphilin-1 may alter
multiple cellular pathways to protect against neuronal degeneration. The
authors concluded that synphilin-1 can diminish the severity of
alpha-synucleinopathy and may play a neuroprotective role against A53T
alpha-synuclein toxicity in vivo.

*FIELD* AV
.0001
PARKINSON DISEASE 1, AUTOSOMAL DOMINANT
SNCA, ALA53THR

In affected members of a large Italian family with an early-onset form
of autosomal dominant Parkinson disease (PARK1; 168601), and in 3 other
unrelated Greek families, Polymeropoulos et al. (1997) demonstrated a
heterozygous ala53-to-thr (A53T) mutation in the SNCA gene, resulting
from a 209G-A transition. The mutation generates a novel Tsp45I
restriction site in the gene.

Vaughan et al. (1998) studied all 7 exons of the SNCA gene in 30
European and American Caucasian kindreds affected with autosomal
dominant PD and found no instance of the A53T mutation or any other
mutation. In a large screening of patients with PD, Farrer et al. (1998)
also found no genetic variation in the SNCA gene. Ho and Kung (1998)
failed to find the A53T missense mutation in 118 Chinese sporadic PD
patients from Hong Kong or 124 control subjects. They also did not find
the mutation in 9 sporadic PD cases from Birmingham, U.K., or 10 control
subjects from the same area.

Athanassiadou et al. (1999) studied 19 unrelated families, each of which
contained at least 2 first- or second-degree relatives affected with PD.
A heterozygous A53T mutation was detected in 10 patients belonging to 7
autosomal dominant families, but was not found in any member of the
remaining 12 families. In patients carrying the mutation, the mean age
at onset of the disorder was 47 +/- 11 years, which was considered to be
early onset. In 1 family, a patient with a much later age at onset of
the disease, 76 years, did not carry the A53T mutation.

In the southern Italian kindred originally reported by Polymeropoulos et
al. (1997) and the 7 Greek families that carried the A53T mutation,
Athanassiadou et al. (1999) studied 10 polymorphic markers. A shared
haplotype was considered consistent with a founder chromosome.
Clinically, the A53T cases, in addition to early age at onset, showed
prominent bradykinesia and muscular rigidity but rarely had tremor. All
7 Greek families with PD studied by Athanassiadou et al. (1999)
originated from 3 villages of the northern Peloponnese in Greece; 6 of
the families were from 2 villages only 17 km apart. The Italian kindred
came from southern Italy, a region geographically and historically
linked to Greece.

Spira et al. (2001) reported a family of Greek origin with 5 of 9 sibs
affected with PD, 3 of whom were examined in detail and were found to
carry the A53T mutation. The 3 sibs presented in their forties with
progressive bradykinesia and rigidity, which was initially
dopa-responsive, and cognitive decline. Additional features included
central hypoventilation, postural hypotension, bladder incontinence, and
myoclonus. Neuropathologic examination showed depigmentation of the
substantia nigra, severe cell loss and gliosis in the brainstem, and
multiple alpha-synuclein-immunopositive Lewy neurites. Cortical neuritic
changes associated with tissue vacuolization were present, mostly in the
medial temporal regions.

Ki et al. (2007) identified a heterozygous A53T mutation in a Korean man
with early-onset PD at age 37 years. A clinically unaffected 45-year-old
brother also carried the mutation. The brothers' mother had onset of PD
at age 63 years and died at age 67; mutation analysis was not performed.
Haplotype analysis showed that this mutation occurred on a different
haplotype from that described in Greek and Italian individuals.

Choi et al. (2008) identified the A53T mutation in 1 of 72 unrelated
Korean patients with onset of Parkinson disease before age 50. Family
history was consistent with autosomal dominant inheritance.

Puschmann et al. (2009) reported 2 affected members of a Swedish family
with the A53T mutation. Haplotype analysis indicated a different
haplotype than the Greek founder haplotype, suggesting a de novo event
in the Swedish family. The proband had insidious onset of decreased
range of motion, stiffness, and hypokinesia between ages 39 and 41
years. About 6 months later, she developed word-finding difficulty and
monotone speech. The disorder was progressive, and she developed
dementia and severe motor disturbances, including myoclonus, by age 47.
Her father developed motor signs of the disorder at age 32, with speech
difficulties at age 33. At age 38, he was moved to a nursing home, and
at 40, he was aphonic with dementia and an inability to walk or feed
himself independently. Both patients had normal brain MRI and increased
CSF protein levels, SPECT scan of the daughter showed decreased blood
flow in the language region. Puschmann et al. (2009) emphasized the
early onset, rapid progression, and presence of dementia in this family,
and suggested that an underlying cortical encephalopathy contributed to
the disease course.

Voutsinas et al. (2010) performed studies on lymphoblastoid cells
derived from a female PD patient who was heterozygous for the A53T
mutation. RT-PCR showed that the mutant A53T protein was not expressed,
and there was only monoallelic expression of the normal SNCA allele.
Treatment of her cells with a chromatin modifier resulted in
reactivation of the silenced mutant allele, indicating that an
epigenetic effect, likely via histone modification, was responsible for
the silencing. There was no evidence for changes in methylation.
Compared to normal individuals, the patient had an average of a 2-fold
increase in total SNCA mRNA. The findings indicated an overall imbalance
of allelic expression of the SNCA gene, with the normal allele expressed
at a higher level than normal. The report was consistent with the
observation that overexpression of the wildtype SNCA gene (see, e.g.,
163890.0005) can also cause Parkinson disease.

.0002
PARKINSON DISEASE 1, AUTOSOMAL DOMINANT
SNCA, ALA30PRO

To investigate further the role of alpha-synuclein in familial Parkinson
disease (168601), Kruger et al. (1998) undertook mutation analysis of
all 5 translated SNCA exons in 192 sporadic cases and in 7 unrelated
patients with a family history for Parkinson disease. None of the
patients was found to carry the A53T mutation (163890.0001). One patient
was found to carry a heterozygous 88G-C transversion in exon 3,
resulting in an ala30-to-pro (A30P) substitution. The index patient
developed signs of progressive parkinsonism at 52 years of age. His
mother presented with symptoms at age 56 and died from the disease at
age 60. A younger sib, aged 55, reported impaired motor function in the
right arm and neurologic findings of Parkinson disease. The 33-year-old
child of the index patient and a 50-year-old sib were carriers of the
mutation. Both exhibited subtle neurologic disturbances. The A30P
substitution was not found in 1,140 control chromosomes. Kruger et al.
(1998) concluded that mutations in the SNCA gene participate in the
pathogenesis of some rare cases of Parkinson disease.

Kruger et al. (2001) characterized the disease phenotype caused by the
A30P mutation and found that it is similar to that of typical PD,
including cardinal features of PD and positive and sustained response to
L-DOPA therapy. Two affected members of 1 family showed striatal
dopaminergic abnormalities on PET scan similar to those in sporadic PD.
Cognitive impairment was noted as an early and frequent finding.

Seidel et al. (2010) reported neuropathologic findings of a patient with
PD due to the A30P mutation. He had onset at age 54 years, had
L-dopa-related complications, and died in a mute, bedridden state at age
69. Postmortem examination showed depigmentation and neuronal loss in
the substantia nigra and neuronal loss in the locus ceruleus and dorsal
motor vagal nucleus. There were widespread SNCA-positive Lewy bodies,
Lewy neurites, and glial aggregates in the cerebral cortex and many
other regions of the brain, including the hippocampus, hypothalamus,
brainstem, and cerebellum. Biochemical analysis showed a significant
load of insoluble SNCA.

Chung et al. (2013) generated cortical neurons from iPS cells of
patients harboring the A53T alpha-synuclein mutation. Genetic modifiers
from unbiased screens in a yeast model of alpha-synuclein toxicity led
to identification of early pathogenic phenotypes in patient neurons,
including nitrosative stress, accumulation of endoplasmic
reticulum-associated degradation substrates, and ER stress. A small
molecule, NAB2, identified in a yeast screen (Tardiff et al., 2013), and
NEDD4 (602278), the ubiquitin ligase that it affects, reversed
pathologic phenotypes in these neurons.

.0003
PARKINSON DISEASE 4, AUTOSOMAL DOMINANT
SNCA, TRIPLICATION

By quantitative PCR amplification of SNCA exons in an individual with
parkinsonism (PARK4; 605543) from a family reported by Waters and Miller
(1994), Singleton et al. (2003) found evidence consistent with whole
gene triplication. Analysis of other family members showed that the SNCA
triplication segregated with parkinsonism, but not with postural tremor.
The authors found that the telomeric end of the triplication occurs
within the model gene KIAA1680 (GenBank GENBANK AB051467), and the
centromeric end occurs between exon 23 of the cyclin E-binding protein
gene (608242) and exon 7 of hypothetical protein DKFZp761G058 (GenBank
GENBANK AK054678). The triplicated region contains an estimated 17
genes, including SNCA. Carriers of the triplication are predicted to
have 4 fully functional copies of SNCA, with doubling of the effective
load of the estimated 17 genes. The authors suggested that increased
dosage of SNCA is the cause of PD in this family, and noted that the
disease process may resemble the etiology of Alzheimer disease in Down
syndrome (190685) with overexpression of the APP gene due to chromosome
21 trisomy.

In affected patients with the SNCA triplication, Miller et al. (2004)
found an approximately 2-fold increase in SNCA protein in blood, a
2-fold increase of SNCA mRNA in brain tissue, and increased levels of
heavily aggregated SNCA protein in brain tissue. The authors concluded
that all 4 alleles were expressed and that increased expression of the
SNCA protein promoted aggregation and deposition in brain tissue, thus
contributing to disease.

Farrer et al. (2004) identified a family of Swedish American descent
with autosomal dominant early-onset parkinsonism and dementia due to a
triplication of the SNCA gene. The phenotype included rapidly
progressive parkinsonism, dysautonomia, and dementia. Fuchs et al.
(2007) determined that the family reported by Farrer et al. (2004) was a
branch of a large family originally reported by Mjones (1949). Fuchs et
al. (2007) identified a Swedish branch of the family who had
parkinsonism and dementia due to a duplication of the SNCA gene
(163890.0005). Genotypes within and flanking the duplicated region in
the Swedish family were identical to genotypes in the Swedish-American
family reported by Farrer et al. (2004), suggesting a common founder.
Hybridization signals indicated a tandem multiplication of the same
genomic interval in the 2 families, a duplication and triplication,
respectively. Sequence analysis indicated that the multiplications were
mediated by centromeric and telomeric long interspersed nuclear element
(LINE L1) motifs.

.0004
DEMENTIA, LEWY BODY
SNCA, GLU46LYS

In affected members of a Spanish family with autosomal dominant Lewy
body dementia (127750) and parkinsonism, Zarranz et al. (2004)
identified a 188G-A transition in the SNCA gene, resulting in a
glu46-to-lys (E46K) substitution in the amino-terminal region of the
protein. The mutation showed complete segregation with the disease
phenotype and was absent in 276 Spanish healthy and disease controls.

Choi et al. (2004) found that the E46K SNCA mutation resulted in a
significant increase in alpha-synuclein binding to negatively charged
phospholipid liposomes compared to the wildtype, A53T (163890.0001), and
A30P (163890.0002) mutant proteins. The A30P mutant had decreased
binding, and the A53T mutant had binding similar to wildtype. The
mutated E46K protein had an increased rate and amount of filament
assembly compared to wildtype and the A30P mutant. The E46K mutant
filaments had a pronounced twisted appearance with width varying between
about 5 and 14 nm and a crossover spacing of 43 nm, yielding arrays with
a meshwork appearance. The A53T mutant had an increased rate and amount
of filament assembly, yielding a twisted appearance with a width between
5 and 14 nm and a crossover spacing of approximately 100 nm. The A30P
mutant showed a slower rate of filament assembly compared to wildtype,
but the total number of filaments formed was greater than wildtype. The
appearance of the A30P filaments was similar to wildtype, characterized
by a 6 to 9-nm width. The findings suggested a mechanism for the
pathogenicity of E46K.

Greenbaum et al. (2005) also showed that the E46K mutation resulted in
increased amyloid fibril assembly compared to the wildtype protein, but
the effect was not as strong as that of the A53T mutation. Synthetic
E46A, E83K, and E83A mutations had the same effect, suggesting that
N-terminal glu residues modulate filament formation.

.0005
PARKINSON DISEASE 1, AUTOSOMAL DOMINANT
DEMENTIA, LEWY BODY, INCLUDED
SNCA, DUPLICATION

In affected members of 3 unrelated families, 2 French and 1 Italian,
with autosomal dominant Parkinson disease (168601), Ibanez et al. (2004)
and Chartier-Harlin et al. (2004) identified heterozygosity for
whole-gene duplication of the SNCA gene. In all patients, the phenotype
was typical for idiopathic PD, with a slightly earlier age at onset (39
to 65 years). Affected individuals had bradykinesia, rigidity, resting
tremor, and a favorable response to levodopa treatment. In contrast to
the family with SNCA triplication (see 163890.0003 and Singleton et al.,
2003), patients with the SNCA duplication did not have signs of dementia
or other atypical features. Ibanez et al. (2004) and Chartier-Harlin et
al. (2004) concluded that there was a clear gene dosage effect that
correlated with the severity of the disease and suggested that genetic
variability within the SNCA promoter may also play a role in the
susceptibility to PD.

Nishioka et al. (2006) identified heterozygosity for duplication of the
SNCA gene in 2 of 113 Japanese probands with autosomal dominant PD. The
length of the duplication in 1 proband was approximately 220 kb,
spanning all of SNCA and exons 1-6 of MMRN1 (601456); in the second
proband, the duplication was approximately 394 kb, spanning all of SNCA
and all of MMRN1. In the first family, 2 patients with the duplication
had typical PD, whereas 4 duplication carriers over the age of 43 years
were unaffected, yielding a penetrance of 33%. In the second family, 1
affected and 2 asymptomatic members had the duplication. The affected
patient from the second family developed dementia 14 years after
diagnosis of PD, and neuropathologic examination (Obi et al., 2008) was
found to be consistent with dementia with Lewy bodies (127750).

Fuchs et al. (2007) reported a Swedish kindred with Parkinson disease
due to a duplication of the SNCA and MMRN1 genes. Clinical features
included autonomic dysfunction and rapidly progressive motor symptoms.
Myoclonus and dementia occurred late in the disease. This family was
determined to be a branch of a large family originally reported by
Mjones (1949). A Swedish American branch of that family was found by
Farrer et al. (2004) to have a triplication of the SNCA gene
(163890.0003). Fuchs et al. (2007) found that genotypes within and
flanking the duplicated region in the Swedish family were identical to
genotypes in the Swedish American family reported by Farrer et al.
(2004), suggesting a common founder. Hybridization signals indicated a
tandem multiplication of the same genomic interval in the 2 families, a
duplication and triplication, respectively. Sequence analysis indicated
that the multiplications were mediated by centromeric and telomeric long
interspersed nuclear element (LINE L1) motifs.

Ahn et al. (2008) identified an SNCA gene duplication in 3 of 906 Korean
patients with Parkinson disease. Only 1 patient had a family history of
the disorder; he presented with early onset at age 40 and rapidly
progressive disease complicated by dementia. Two of his brothers with
the duplication were asymptomatic at 51 and 47 years, respectively,
indicating reduced penetrance.

Brueggemann et al. (2008) and Troiano et al. (2008) independently
identified duplications of the SNCA gene in 2 patients with sporadic
early-onset PD, at ages 36 and 35 years, respectively. The mutation was
confirmed to be de novo in the case of Brueggemann et al. (2008).
Neither patient had cognitive impairment. The prevalence of the SNCA
duplication in sporadic PD was reported to be 0.25% and 1%,
respectively.

Uchiyama et al. (2008) reported a Japanese mother and son with
duplication of the SNCA gene associated with variable features of
parkinsonism and dementia. The son had prominent parkinsonism in his
late forties, followed by fluctuating cognitive decline, visual
hallucinations, and deficits in verbal fluency a few years later. The
mother presented later at age 72 with memory disturbances and
fluctuating cognitive deficits. She then developed mild parkinsonism and
visual hallucinations. PET studies showed that both patients had diffuse
hypometabolism in the brain that extended to the occipital visual cortex
in the mother. Uchiyama et al. (2008) noted that the diagnoses in the
son and mother were compatible with PD dementia and Lewy body dementia,
respectively.

.0006
PARKINSON DISEASE 1, AUTOSOMAL DOMINANT
SNCA, GLY51ASP

In 4 members of a French family with autosomal dominant PD (168601) and
spasticity, Lesage et al. (2013) identified a heterozygous c.152G-A
transition in the SNCA gene, resulting in a gly51-to-asp (G51D)
substitution at a highly conserved residue. The mutation, which was
found by whole-exome sequencing and confirmed by Sanger sequencing,
segregated with the disorder in the family. It was not present in the
dbSNP (build 132), 1000 Genomes Project, or Exome Sequencing Project
databases, or in 236 control individuals. In vitro cellular expression
studies showed that the mutant G51D protein assembled into high
molecular weight fibrils in a concentration-dependent manner, similar to
wildtype and to A53T (163890.0001). Sedimentation velocity experiments
showed that the proportion of oligomeric G51D SNCA in solution was
significantly lower than that of wildtype or A53T. Mutant G51D and
wildtype SNCA coassembled, such that fibrils of each protein seeded
soluble oligomer assembly of the other. Fibrillar G51D decreased cell
survival by enhancing caspase-3 (CASP3; 600636) activity. The patients
had a unique disorder comprising rapidly progressive Parkinson disease,
spasticity, and psychiatric features. Three affected individuals had
onset at age 31 to 35 years, whereas the fourth had onset at age 60. The
disorder was rapidly progressive: all became bedridden within 5 to 7
years, and 3 patients died within 5 to 7 years of onset. Neuropathologic
examination of 1 patient showed neuronal loss in the substantia nigra
and striatum, as well as astrogliosis. There was also neuronal loss in
the motor cortex, the anterior horn of the spinal cord, and the
corticospinal tracts. Lewy bodies and dystrophic Lewy neurites were
present mostly in the brainstem. There were fine, diffuse, neuronal
cytoplasmic inclusions in all superficial cortical layers. Lesage et al.
(2013) suggested that the structural and aggregative properties of the
mutant protein did not fully account for the pathology, and postulated
that undefined abnormal protein interactions may also have contributed.

*FIELD* RF
1. Abeliovich, A.; Schmitz, Y.; Farinas, I.; Choi-Lundberg, D.; Ho,
W.-H.; Castillo, P. E.; Shinsky, N.; Verdugo, J. M. G.; Armanini,
M.; Ryan, A.; Hynes, M.; Phillips, H.; Sulzer, D.; Rosenthal, A.:
Mice lacking alpha-synuclein display functional deficits in the nigrostriatal
dopamine system. Neuron 25: 239-252, 2000.

2. Ahn, T.-B.; Kim, S. Y.; Kim, J. Y.; Park, S.-S.; Lee, D. S.; Min,
H. J.; Kim, Y. K.; Kim, S. E.; Kim, J.-M.; Kim, H.-J.; Cho, J.; Jeon,
B. S.: Alpha-synuclein gene duplication is present in sporadic Parkinson
disease. Neurology 70: 43-49, 2008.

3. Anderson, J. P.; Walker, D. E.; Goldstein, J. M.; de Laat, R.;
Banducci, K.; Caccavello, R. J.; Barbour, R.; Huang, J.; Kling, K.;
Lee, M.; Diep, L.; Keim, P. S.; Shen, X.; Chataway, T.; Schlossmacher,
M. G.; Seubert, P.; Schenk, D.; Sinha, S.; Gai, W. P.; Chilcote, T.
J.: Phosphorylation of ser-129 is the dominant pathological modification
of alpha-synuclein in familial and sporadic Lewy body disease. J.
Biol. Chem. 281: 29739-29752, 2006.

4. Athanassiadou, A.; Voutsinas, G.; Psiouri, L.; Leroy, E.; Polymeropoulos,
M. H.; Ilias, A.; Maniatis, G. M.; Papapetropoulos, T.: Genetic analysis
of families with Parkinson disease that carry the ala53-to-thr mutation
in the gene encoding alpha-synuclein. (Letter) Am. J. Hum. Genet. 65:
555-558, 1999.

5. Auluck, P. K.; Chan, H. Y. E.; Trojanowski, J. Q.; Lee, V. M.-Y.;
Bonini, N. M.: Chaperone suppression of alpha-synuclein toxicity
in a Drosophila model for Parkinson's disease. Science 295: 865-868,
2002.

6. Bartels, T.; Choi, J. G.; Selkoe, D. J.: Alpha-synuclein occurs
physiologically as a helically folded tetramer that resists aggregation. Nature 477:
107-110, 2011.

7. Bertoncini, C. W.; Fernandez, C. O.; Griesinger, C.; Jovin, T.
M.; Zweckstetter, M.: Familial mutants of alpha-synuclein with increased
neurotoxicity have a destabilized conformation. J. Biol. Chem. 280:
30649-30652, 2005.

8. Beyer, K.; Domingo-Sabat, M.; Lao, J. I.; Carrato, C.; Ferrer,
I.; Ariza, A.: Identification and characterization of a new alpha-synuclein
isoform and its role in Lewy body diseases. Neurogenetics 9: 15-23,
2008.

9. Bonsch, D.; Lederer, T.; Reulbach, U.; Hothorn, T.; Kornhuber,
J.; Bleich, S.: Joint analysis of the NACP-REP1 marker within the
alpha synuclein gene concludes association with alcohol dependence. Hum.
Molec. Genet. 14: 967-971, 2005.

10. Brueggemann, N.; Odin, P.; Gruenewald, A.; Tadic, V.; Hagenah,
J.; Seidel, G.; Lohmann, K.; Klein, C.; Djarmati, A.: Alpha-synuclein
gene duplication is present in sporadic Parkinson disease. (Letter) Neurology 71:
1294 only, 2008.

11. Burre, J.; Sharma, M.; Tsetsenis, T.; Buchman, V.; Etherton, M.
R.; Sudhof, T. C.: Alpha-synuclein promotes SNARE-complex assembly
in vivo and in vitro. Science 329: 1663-1667, 2010.

12. Campion, D.; Martin, C.; Heilig, R.; Charbonnier, F.; Moreau,
V.; Flaman, J. M.; Petit, J. L.; Hannequin, D.; Brice, A.; Frebourg,
T.: The NACP/synuclein gene: chromosomal assignment and screening
for alterations in Alzheimer disease. Genomics 26: 254-257, 1995.

13. Chartier-Harlin, M.-C.; Kachergus, J.; Roumier, C.; Mouroux, V.;
Douay, X.; Lincoln, S.; Levecque, C.; Larvor, L.; Andrieux, J.; Hulihan,
M.; Waucquier, N.; Defebvre, L.; Amouyel, P.; Farrer, M.; Destee,
A.: Alpha-synuclein locus duplication as a cause of familial Parkinson's
disease. Lancet 364: 1167-1169, 2004.

14. Chen, L.; Feany, M. B.: Alpha-synuclein phosphorylation controls
neurotoxicity and inclusion formation in a Drosophila model of Parkinson
disease. Nature Neurosci. 8: 657-663, 2005.

15. Chen, X.; Rohan de Silva, H. A.; Pettenati, M. J.; Rao, P. N.;
St. George-Hyslop, P.; Roses, A. D.; Xia, Y.; Horsburgh, K.; Ueda,
K.; Saitoh, T.: The human NACP/alpha-synuclein gene: chromosome assignment
to 4q21.3-q22 and TaqI RFLP analysis. Genomics 26: 425-427, 1995.

16. Chiba-Falek, O.; Kowalak, J. A.; Smulson, M. E.; Nussbaum, R.
L.: Regulation of alpha-synuclein expression by poly (ADP ribose)
polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream
of the SNCA gene. Am. J. Hum. Genet. 76: 478-492, 2005.

17. Chiba-Falek, O.; Nussbaum, R. L.: Effect of allelic variation
at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA)
on transcription in a cell culture luciferase reporter system. Hum.
Molec. Genet. 10: 3101-3109, 2001.

18. Chiba-Falek, O.; Touchman, J. W.; Nussbaum, R. L.: Functional
analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein
gene. Hum. Genet. 113: 426-431, 2003.

19. Choi, J. M.; Woo, M. S.; Ma, H.-I.; Kang, S. Y.; Sung, Y.-H.;
Yong, S. W.; Chung, S. J.; Kim, J.-S.; Shin, H.; Lyoo, C. H.; Lee,
P. H.; Baik, J. S.; and 9 others: Analysis of PARK genes in a Korean
cohort of early-onset Parkinson disease. Neurogenetics 9: 263-269,
2008.

20. Choi, W.; Zibaee, S.; Jakes, R.; Serpell, L. C.; Davletov, B.;
Crowther, R. A.; Goedert, M.: Mutation E46K increases phospholipid
binding and assembly into filaments of human alpha-synuclein. FEBS
Lett. 576: 363-368, 2004.

21. Chung, C. Y.; Khurana, V.; Auluck, P. K.; Tardiff, D. F.; Mazzulli,
J. R.; Soldner, F.; Baru, V.; Lou, Y.; Freyzon, Y.; Cho, S.; Mungenast,
A. E.; Muffat, J.; and 10 others: Identification and rescue of
alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342:
983-987, 2013.

22. Chung, K. K. K.; Zhang, Y.; Lim, K. L.; Tanaka, Y.; Huang, H.;
Gao, J.; Ross, C. A.; Dawson, V. L.; Dawson, T. M.: Parkin ubiquitinates
the alpha-synuclein-interacting protein, synphilin-1: implications
for Lewy-body formation in Parkinson disease. Nature Med. 7: 1144-1150,
2001.

23. Conway, K. A.; Lee, S.-J.; Rochet, J.-C.; Ding, T. T.; Williamson,
R. E.; Lansbury, P. T., Jr.: Acceleration of oligomerization, not
fibrillization, is a shared property of both alpha-synuclein mutations
linked to early-onset Parkinson's disease: implications for pathogenesis
and therapy. Proc. Nat. Acad. Sci. 97: 571-576, 2000.

24. Cooper, A. A.; Gitler, A. D.; Cashikar, A.; Haynes, C. M.; Hill,
K. J.; Bhullar, B.; Liu, K.; Xu, K.; Strathearn, K. E.; Liu, F.; Cao,
S.; Caldwell, K. A.; Caldwell, G. A.; Marsischky, G.; Kolodner, R.
D.; LaBaer, J.; Rochet, J.-C.; Bonini, N. M.; Lindquist, S.: Alpha-synuclein
blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's
models. Science 313: 324-328, 2006.

25. Cronin, K. D.; Ge, D.; Manninger, P.; Linnertz, C.; Rossoshek,
A.; Orrison, B. M.; Bernard, D. J.; El-Agnaf, O. M. A.; Schlossmacher,
M. G.; Nussbaum, R. L.; Chiba-Falek, O.: Expansion of the Parkinson
disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein
in transgenic mouse brain. Hum. Molec. Genet. 18: 3274-3285, 2009.

26. Cuervo, A. M.; Stefanis, L.; Fredenburg, R.; Lansbury, P. T.;
Sulzer, D.: Impaired degradation of mutant alpha-synuclein by chaperone-mediated
autophagy. Science 305: 1292-1295, 2004.

27. da Costa, C. A.; Paitel, E.; Vincent, B.; Checler, F.: Alpha-synuclein
lowers p53-dependent apoptotic response of neuronal cells: abolishment
by 6-hydroxydopamine and implication for Parkinson's disease. J.
Biol. Chem. 277: 50980-50984, 2002.

28. da Silveira, S. A.; Schneider, B. L.; Cifuentes-Diaz, C.; Sage,
D.; Abbas-Terki, T.; Iwatsubo, T.; Unser, M.; Aebischer, P.: Phosphorylation
does not prompt, nor prevent, the formation of alpha-synuclein toxic
species in a rat model of Parkinson's disease. Hum. Molec. Genet. 18:
872-887, 2009.

29. Dauer, W.; Kholodilov, N.; Vila, M.; Trillat, A.-C.; Goodchild,
R.; Larsen, K. E.; Staal, R.; Tieu, K.; Schmitz, Y.; Yuan, C. A.;
Rocha, M.; Jackson-Lewis, V.; Hersch, S.; Sulzer, D.; Przedborski,
S.; Burke, R.; Hen, R.: Resistance of alpha-synuclein null mice to
the parkinsonian neurotoxin MPTP. Proc. Nat. Acad. Sci. 99: 14524-14529,
2002.

30. Elbaz, A.; Ross, O. A.; Ioannidis, J. P. A.; Soto-Ortolaza, A.
I.; Moisan, F.; Aasly, J.; Annesi, G.; Bozi, M.; Brighina, L.; Chartier-Harlin,
M.-C.; Destee, A.; Ferrarese, C.; and 29 others: Independent and
joint effects of the MAPT and SNCA genes in Parkinson disease. Ann.
Neurol. 69: 778-792, 2011.

31. Engelender, S.; Kaminsky, Z.; Guo, X.; Sharp, A. H.; Amaravi,
R. K.; Kleiderlein, J. J.; Margolis, R. L.; Troncoso, J. C.; Lanahan,
A. A.; Worley, P. F.; Dawson, V. L.; Dawson, T. M.; Ross, C. A.:
Synphilin-1 associates with alpha-synuclein and promotes the formation
of cytosolic inclusions. Nature Genet. 22: 110-114, 1999.

32. Farrer, M.; Kachergus, J.; Forno, L.; Lincoln, S.; Wang, D.-S.;
Hulihan, M.; Maraganore, D.; Gwinn-Hardy, K.; Wszolek, Z.; Dickson,
D.; Langston, J. W.: Comparison of kindreds with parkinsonism and
alpha-synuclein genomic multiplications. Ann. Neurol. 55: 174-179,
2004.

33. Farrer, M.; Wavrant-De Vrieze, F.; Crook, R.; Boles, L.; Perez-Tur,
J.; Hardy, J.; Johnson, W. G.; Steele, J.; Maraganore, D.; Gwinn,
K.; Lynch, T.: Low frequency of alpha-synuclein mutations in familial
Parkinson's disease. Ann. Neurol. 43: 394-397, 1998.

34. Feany, M. B.; Bender, W. W.: A Drosophila model of Parkinson's
disease. Nature 404: 394-398, 2000.

35. Fuchs, J.; Nilsson, C.; Kachergus, J.; Munz, M.; Larsson, E.-M.;
Schule, B.; Langston, J. W.; Middleton, F. A.; Ross, O. A.; Hulihan,
M.; Gasser, T.; Farrer, M. J.: Phenotypic variation in a large Swedish
pedigree due to SNCA duplication and triplication. Neurology 68:
916-922, 2007.

36. Fujiwara, H.; Hasegawa, M.; Dohmae, N.; Kawashima, A.; Masliah,
E.; Goldberg, M. S.; Shen, J.; Takio, K.; Iwatsubo, T.: Alpha-synuclein
is phosphorylated in synucleinopathy lesions. Nature Cell Biol. 4:
160-164, 2002.

37. George, J. M.; Jin, H.; Woods, W. S.; Clayton, D. F.: Characterization
of a novel protein regulated during the critical period for song learning
in the zebra finch. Neuron 15: 361-372, 1995.

38. Giasson, B. I.; Duda, J. E.; Murray, I. V. J.; Chen, Q.; Souza,
J. M.; Hurtig, H. I.; Ischiropoulos, H.; Trojanowski, J. Q.; Lee,
V. M.-Y.: Oxidative damage linked to neurodegeneration by selective
alpha-synuclein nitration in synucleinopathy lesions. Science 290:
985-989, 2000.

39. Giasson, B. I.; Forman, M. S.; Higuchi, M.; Golbe, L. I.; Graves,
C. L.; Kotzbauer, P. T.; Trojanowski, J. Q.; Lee, V. M.-Y.: Initiation
and synergistic fibrillization of tau and alpha-synuclein. Science 300:
636-640, 2003.

40. Gitler, A. D.; Chesi, A.; Geddie, M. L.; Strathearn, K. E.; Hamamichi,
S.; Hill, K. J.; Caldwell, K. A.; Caldwell, G. A.; Cooper, A. A.;
Rochet, J.-C.; Lindquist, S.: Alpha-synuclein is part of a diverse
and highly conserved interaction network that includes PARK9 and manganese
toxicity. Nature Genet. 41: 308-315, 2009.

41. Goedert, M.: The awakening of alpha-synuclein. Nature 388:
232-233, 1997.

42. Goris, A.; Williams-Gray, C. H.; Clark, G. R.; Foltynie, T.; Lewis,
S. J. G.; Brown, J.; Ban, M.; Spillantini, M. G.; Compston, A.; Burn,
D. J.; Chinnery, P. F.; Barker, R. A.; Sawcer, S. J.: Tau and alpha-synuclein
in susceptibility to, and dementia in, Parkinson's disease. Ann.
Neurol. 62: 145-153, 2007.

43. Greenbaum, E. A.; Graves, C. L.; Mishizen-Eberz, A. J.; Lupoli,
M. A.; Lynch, D. R.; Englander, S. W.; Axelsen, P. H.; Giasson, B.
I.: The E46K mutation in alpha-synuclein increases amyloid fibril
formation. J. Biol. Chem. 280: 7800-7807, 2005.

44. Hartz, P. A.: Personal Communication. Baltimore, Md. 8/4/2010.

45. Heintz, N.; Zoghbi, H.: Alpha-synuclein--a link between Parkinson
and Alzheimer diseases? Nature Genet. 16: 325-327, 1997.

46. Ho, S.-L.; Kung, M. H. W.: G209A mutation in the alpha-synuclein
gene is rare and not associated with sporadic Parkinson's disease. Mov.
Disord. 13: 970-971, 1998.

47. Ibanez, P.; Bonnet, A.-M.; Debarges, B.; Lohmann, E.; Tison, F.;
Pollak, P.; Agid, Y.; Durr, A.; Brice, A.; French Parkinson's disease
genetics study group: Causal relation between alpha-synuclein gene
duplication and familial Parkinson's disease. Lancet 364: 1169-1171,
2004.

48. Ibanez, P.; Lesage, S.; Janin, S.; Lohmann, E.; Durif, F.; Destee,
A.; Bonnet, A.-M.; Brefel-Courbon, C.; Heath, S.; Zelenika, D.; Agid,
Y.; Durr, A.; Brice, A.: Alpha-synuclein gene rearrangements in dominantly
inherited Parkinsonism. Arch. Neurol. 66: 102-108, 2009.

49. Ihara, M.; Yamasaki, N.; Hagiwara, A.; Tanigaki, A.; Kitano, A.;
Hikawa, R.; Tomimoto, H.; Noda, M.; Takanashi, M.; Mori, H.; Hattori,
N.; Miyakawa, T.; Kinoshita, M.: Sept4, a component of presynaptic
scaffold and Lewy bodies, is required for the suppression of alpha-synuclein
neurotoxicity. Neuron 53: 519-533, 2007.

50. Iwata, A.; Maruyama, M.; Akagi, T.; Hashikawa, T.; Kanazawa, I.;
Tsuji, S.; Nukina, N.: Alpha-synuclein degradation by serine protease
neurosin: implication for pathogenesis of synucleinopathies. Hum.
Molec. Genet. 12: 2625-2635, 2003.

51. Jakes, R.; Spillantini, M. G.; Goedert, M.: Identification of
two distinct synucleins from human brain. FEBS Lett. 345: 27-32,
1994.

52. Johnson, J.; Hague, S. M.; Hanson, M.; Gibson, A.; Wilson, K.
E.; Evans, E. W.; Singleton, A. A.; McInerney-Leo, A.; Nussbaum, R.
L.; Hernandez, D. G.; Gallardo, M.; McKeith, I. G.; Burn, D. J.; Ryu,
M.; Hellstrom, O.; Ravina, B.; Eerola, J.; Perry, R. H.; Jaros, E.;
Tienari, P.; Weiser, R.; Gwinn-Hardy, K.; Morris, C. M.; Hardy, J.;
Singleton, A. B.: SNCA multiplication is not a common cause of Parkinson
disease or dementia with Lewy bodies. Neurology 63: 554-556, 2004.

53. Junn, E.; Ronchetti, R. D.; Quezado, M. M.; Kim, S.-Y.; Mouradian,
M. M.: Tissue transglutaminase-induced aggregation of alpha-synuclein:
implications for Lewy body formation in Parkinson's disease and dementia
with Lewy bodies. Proc. Nat. Acad. Sci. 100: 2047-2052, 2003.

54. Kawahara, K.; Hashimoto, M.; Bar-On, P.; Ho, G. J.; Crews, L.;
Mizuno, H.; Rockenstein, E.; Imam, S. Z.; Masliah, E.: Alpha-synuclein
aggregates interfere with parkin solubility and distribution: role
in the pathogenesis of Parkinson disease. J. Biol. Chem. 283: 6979-6987,
2008.

55. Ki, C.-S.; Stavrou, E. F.; Davanos, N.; Lee, W. Y.; Chung, E.
J.; Kim, J.-Y.; Athanassiadou, A.: The ala53thr mutation in the alpha-synuclein
gene in a Korean family with Parkinson disease. (Letter) Clin. Genet. 71:
471-473, 2007.

56. Kruger, R.; Kuhn, W.; Leenders, K. L.; Sprengelmeyer, R.; Muller,
T.; Woitalla, D.; Portman, A. T.; Maguire, R. P.; Veenma, L.; Schroder,
U.; Schols, L.; Epplen, J. T.; Riess, O.; Przuntek, H.: Familial
parkinsonism with synuclein pathology: clinical and PET studies of
A30P mutation carriers. Neurology 56: 1355-1362, 2001.

57. Kruger, R.; Kuhn, W.; Muller, T.; Woitalla, D.; Graeber, M.; Kosel,
S.; Przuntek, H.; Epplen, J. T.; Schols, L.; Riess, O.: Ala30-to-pro
mutation in the gene encoding alpha-synuclein in Parkinson's disease.
(Letter) Nature Genet. 18: 106-108, 1998.

58. Kuo, Y.-M.; Li, Z.; Jiao, Y.; Gaborit, N.; Pani, A. K.; Orrison,
B. M.; Bruneau, B. G.; Giasson, B. I.; Smeyne, R. J.; Gershon, M.
D.; Nussbaum, R. L.: Extensive enteric nervous system abnormalities
in mice transgenic for artificial chromosomes containing Parkinson
disease-associated alpha-synuclein gene mutations precede central
nervous system changes. Hum. Molec. Genet. 19: 1633-1650, 2010.

59. Lashuel, H. A.; Hartley, D.; Petre, B. M.; Walz, T.; Lansbury,
P. T., Jr.: Amyloid pores from pathogenic mutations. Nature 418:
291 only, 2002.

60. Lee, J. T.; Wheeler, T. C.; Li, L.; Chin, L.-S.: Ubiquitination
of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation
and apoptotic cell death. Hum. Molec. Genet. 17: 906-917, 2008.

61. Lee, M. K.; Stirling, W.; Xu, Y.; Xu, X.; Qui, D.; Mandir, A.
S.; Dawson, T. M.; Copeland, N. G.; Jenkins, N. A.; Price, D. L.:
Human alpha-synuclein-harboring familial Parkinson's disease-linked
ala53-to-thr mutation causes neurodegenerative disease with alpha-synuclein
aggregation in transgenic mice. Proc. Nat. Acad. Sci. 99: 8968-8973,
2002.

62. Lesage, S.; Anheim, M.; Letournel, F.; Bousset, L.; Honore, A.;
Rozas, N.; Pieri, L.; Madiona, K.; Durr, A.; Melki, R.; Verny, C.;
Brice, A.: G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal
syndrome. Ann. Neurol. 73: 459-471, 2013.

63. Liang, T.; Spence, J.; Liu, L.; Strother, W. N.; Chang, H. W.;
Ellison, J. A.; Lumeng, L.; Li, T.-K.; Foroud, T.; Carr, L. G.: Alpha-synuclein
maps to a quantitative trait locus for alcohol preference and is differentially
expressed in alcohol-preferring and -nonpreferring rats. Proc. Nat.
Acad. Sci. 100: 4690-4695, 2003.

64. Liani, E.; Eyal, A.; Avraham, E.; Shemer, R.; Szargel, R.; Berg,
D.; Bornemann, A.; Riess, O.; Ross, C. A.; Rott, R.; Engelender, S.
: Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its
presence in cellular inclusions and Lewy bodies imply a role in Parkinson's
disease. Proc. Nat. Acad. Sci. 101: 5500-5505, 2004.

65. Lin, X.; Parisiadou, L.; Gu, X.-L.; Wang, L.; Shim, H.; Sun, L.;
Xie, C.; Long, C.-X.; Yang, W.-J.; Ding, J.; Chen, Z. Z.; Gallant,
P. E.; Tao-Cheng, J.-H.; Rudow, G.; Troncoso, J. C.; Liu, Z.; Li,
Z.; Cai, H.: Leucine-rich repeat kinase 2 regulates the progression
of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64:
807-827, 2009.

66. Liu, S.; Ninan, I.; Antonova, I.; Battaglia, F.; Trinchese, F.;
Narasanna, A.; Kolodilov, N.; Dauer, W.; Hawkins, R. D.; Arancio,
O.: Alpha-synuclein produces a long-lasting increase in neurotransmitter
release. EMBO J. 23: 4506-4516, 2004.

67. Lotharius, J.; Brundin, P.: Impaired dopamine storage resulting
from alpha-synuclein mutations may contribute to the pathogenesis
of Parkinson's disease. Hum. Molec. Genet. 11: 2395-2407, 2002.

68. Luk, K. C.; Kehm, V.; Carroll, J.; Zhang, B.; O'Brien, P.; Trojanowski,
J. Q.; Lee, V. M.-Y.: Pathological alpha-synuclein transmission initiates
Parkinson-like neurodegeneration in nontransgenic mice. Science 338:
949-953, 2012.

69. Mamah, C. E.; Lesnick, T. G.; Lincoln, S. J.; Strain, K. J.; de
Andrade, M.; Bower, J. H.; Ahlskog, J. E.; Rocca, W. A.; Farrer, M.
J.; Maraganore, D. M.: Interaction of alpha-synuclein and tau genotypes
in Parkinson's disease. Ann. Neurol. 57: 439-443, 2005.

70. Maraganore, D. M.; de Andrade, M.; Elbaz, A.; Farrer, M. J.; Ioannidis,
J. P.; Kruger, R.; Rocca, W. A.; Schneider, N. K.; Lesnick, T. G.;
Lincoln, S. J.; Hulihan, M. M.; Aasly, J. O.; and 16 others: Collaborative
analysis of alpha-synuclein gene promoter variability and Parkinson
disease. JAMA 296: 661-670, 2006.

71. Markopoulou, K.; Wszolek, Z. K.; Pfeiffer, R. F.: A Greek-American
kindred with autosomal dominant, levodopa-responsive Parkinsonism
and anticipation. Ann. Neurol. 38: 373-378, 1995.

72. Maroteaux, L.; Scheller, R. H.: The rat brain synucleins: family
of proteins transiently associated with neuronal membrane. Molec.
Brain Res. 11: 335-343, 1991.

73. Martinez, J.; Moeller, I.; Erdjument-Bromage, H.; Tempst, P.;
Lauring, B.: Parkinson's disease-associated alpha-synuclein is a
calmodulin substrate. J. Biol. Chem. 278: 17379-17387, 2003.

74. Masliah, E.; Rockenstein, E.; Veinbergs, I.; Mallory, M.; Hashimoto,
M.; Takeda, A.; Sagara, Y.; Sisk, A.; Mucke, L.: Dopaminergic loss
and inclusion body formation in alpha-synuclein mice: implications
for neurodegenerative disorders. Science 287: 1265-1269, 2000.

75. Masliah, E.; Rockenstein, E.; Veinbergs, I.; Sagara, Y.; Mallory,
M.; Hashimoto, M.; Mucke, L.: Beta-amyloid peptides enhance alpha-synuclein
accumulation and neuronal deficits in a transgenic mouse model linking
Alzheimer's disease and Parkinson's disease. Proc. Nat. Acad. Sci. 98:
12245-12250, 2001.

76. Mazzulli, J. R.; Xu, Y.-H.; Sun, Y.; Knight, A. L.; McLean, P.
J.; Caldwell, G. A.; Sidransky, E.; Grabowski, G. A.; Krainc, D.:
Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional
pathogenic loop in synucleinopathies. Cell 146: 37-52, 2011.

77. Miller, D. W.; Hague, S. M.; Clarimon, J.; Baptista, M.; Gwinn-Hardy,
K.; Cookson, M. R.; Singleton, A. B.: Alpha-synuclein in blood and
brain from familial Parkinson disease with SNCA locus triplication. Neurology 62:
1835-1838, 2004.

78. Mjones, H.: Paralysis agitans: a clinical and genetic study. Acta
Psychiat. Neurol. 54: 1-195, 1949.

79. Mueller, J. C.; Fuchs, J.; Hofer, A.; Zimprich, A.; Lichtner,
P.; Illig, T.; Berg, D.; Wullner, U.; Meitinger, T.; Gasser, T.:
Multiple regions of alpha-synuclein are associated with Parkinson's
disease. Ann. Neurol. 57: 535-541, 2005.

80. Nakai, M.; Fujita, M.; Waragai, M.; Sugama, S.; Wei, J.; Akatsu,
H.; Ohtaka-Maruyama, C.; Okado, H.; Hashimoto, M.: Expression of
alpha-synuclein, a presynaptic protein implicated in Parkinson's disease,
in erythropoietic lineage. Biochem. Biophys. Res. Commun. 358: 104-110,
2007.

81. Nakamura, K.; Nemani, V. M.; Azarbal, F.; Skibinski, G.; Levy,
J. M.; Egami, K.; Munishkina, L.; Zhang, J.; Gardner, B.; Wakabayashi,
J.; Sesaki, H.; Cheng, Y.; Finkbeiner, S.; Nussbaum, R. L.; Masliah,
E.; Edwards, R. H.: Direct membrane association drives mitochondrial
fission by the Parkinson disease-associated protein alpha-synuclein. J.
Biol. Chem. 286: 20710-20726, 2011.

82. Narhi, L.; Wood, S. J.; Steavenson, S.; Jiang, Y.; Wu, G. M.;
Anafi, D.; Kaufman, S. A.; Martin, F.; Sitney, K.; Denis, P.; Louis,
J.-C.; Wypych, J.; Biere, A. L.; Citron, M.: Both familial Parkinson's
disease mutations accelerate alpha-synuclein aggregation. J. Biol.
Chem. 274: 9843-9846, 1999. Note: Erratum: J. Biol. Chem. 274: 13728
only, 1999.

83. Nemani, V. M.; Lu, W.; Berge, V.; Nakamura, K.; Onoa, B.; Lee,
M. K.; Chaudhry, F. A.; Nicoll, R. A.; Edwards, R. H.: Increased
expression of alpha-synuclein reduces neurotransmitter release by
inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:
66-79, 2010.

84. Nishioka, K.; Hayashi, S.; Farrer, M. J.; Singleton, A. B.; Yoshino,
H.; Imai, H.; Kitami, T.; Sato, K.; Kuroda, R.; Tomiyama, H.; Mizoguchi,
K.; Murata, M.; Toda, T.; Imoto, I.; Inazawa, J.; Mizuno, Y.; Hattori,
N.: Clinical heterogeneity of alpha-synuclein gene duplication in
Parkinson's disease. Ann. Neurol. 59: 298-309, 2006.

85. Obi, T.; Nishioka, K.; Ross, O. A.; Terada, T.; Yamazaki, K.;
Sugiura, A.; Takanashi, M.; Mizoguchi, K.; Mori, H.; Mizuno, Y.; Hattori,
N.: Clinicopathologic study of a SNCA gene duplication patient with
parkinson disease and dementia. Neurology 70: 238-241, 2008.

86. Outeiro, T. F.; Kontopoulous, E.; Altmann, S. M.; Kufareva, I.;
Strathearn, K. E.; Amore, A. M.; Volk, C. B.; Maxwell, M. M.; Rochet,
J.-C.; McLean, P. J.; Young, A. B.; Abagyan, R.; Feany, M. B.; Hyman,
B. T.; Kazantsev, A. G.: Sirtuin 2 inhibitors rescue alpha-synuclein-mediated
toxicity in models of Parkinson's disease. Science 317: 516-519,
2007.

87. Outeiro, T. F.; Lindquist, S.: Yeast cells provide insight into
alpha-synuclein biology and pathobiology. Science 302: 1772-1775,
2003.

88. Pals, P.; Lincoln, S.; Manning, J.; Heckman, M.; Skipper, L.;
Hulihan, M.; Van den Broeck, M.; De Pooter, T.; Cras, P.; Crook, J.;
Van Broeckhoven, C.; Farrer, M. J.: Alpha-synuclein promoter confers
susceptibility to Parkinson's disease. Ann. Neurol. 56: 591-595,
2004.

89. Petrucelli, L.; O'Farrell, C.; Lockhart, P. J.; Baptista, M.;
Kehoe, K.; Vink, L.; Choi, P.; Wolozin, B.; Farrer, M.; Hardy, J.;
Cookson, M. R.: Parkin protects against the toxicity associated with
mutant alpha-synuclein: proteasome dysfunction selectively affects
catecholaminergic neurons. Neuron 36: 1007-1019, 2002.

90. Polymeropoulos, M. H.; Higgins, J. J.; Golbe, L. I.; Johnson,
W. G.; Ide, S. E.; Di Iorio, G.; Sanges, G.; Stenroos, E. S.; Pho,
L. T.; Schaffer, A. A.; Lazzarini, A. M.; Nussbaum, R. L.; Duvoisin,
R. C.: Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 274:
1197-1198, 1996.

91. Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.; Dehejia,
A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; Stenroos,
E. S.; Chandrasekharappa, S.; Athanassiadou, A.; Papepetropoulos,
T.; Johnson, W. G.; Lazzarini, A. M.; Duvoisin, R. C.; Di Iorio, G.;
Golbe, L. I.; Nussbaum, R. L.: Mutation in the alpha-synuclein gene
identified in families with Parkinson's disease. Science 276: 2045-2047,
1997.

92. Puschmann, A.; Ross, O. A.; Vilarino-Guell, C.; Lincoln, S. J.;
Kachergus, J. M.; Cobb, S. A.; Lindquist, S. G.; Nielsen, J. E.; Wszolek,
Z. K.; Farrer, M.; Widner, H.; van Westen, D.; Hagerstrom, D.; Markopoulou,
K.; Chase, B. A.; Nilsson, K.; Reimer, J.; Nilsson, C.: A Swedish
family with de novo alpha-synuclein A53T mutation: evidence for early
cortical dysfunction. Parkinsonism Relat. Disord. 15: 627-632, 2009.

93. Ramsey, C. P.; Tsika, E.; Ischiropoulos, H.; Giasson, B. I.:
DJ-1 deficient mice demonstrate similar vulnerability to pathogenic
ala53-to-thr human alpha-syn toxicity. Hum. Molec. Genet. 19: 1425-1437,
2010.

94. Ross, O. A.; Braithwaite, A. T.; Skipper, L. M.; Kachergus, J.;
Hulihan, M. M.; Middleton, F. A.; Nishioka, K.; Fuchs, J.; Gasser,
T.; Maraganore, D. M.; Adler, C. H.; Larvor, L.; Chartier-Harlin,
M.-C.; Nilsson, C.; Langston, J. W.; Gwinn, K.; Hattori, N.; Farrer,
M. J.: Genomic investigation of alpha-synuclein multiplication and
parkinsonism. Ann. Neurol. 63: 743-750, 2008.

95. Scherzer, C. R.; Grass, J. A.; Liao, Z.; Pepivani, I.; Zheng,
B.; Eklund, A. C.; Ney, P. A.; Ng, J.; McGoldrick, M.; Mollenhauer,
B.; Bresnick, E. H.; Schlossmacher, M. G.: GATA transcription factors
directly regulate the Parkinson's disease-linked gene alpha-synuclein. Proc.
Nat. Acad. Sci. 105: 10907-10912, 2008.

96. Scherzer, C. R.; Jensen, R. V.; Gullans, S. R.; Feany, M. B.:
Gene expression changes presage neurodegeneration in a Drosophila
model of Parkinson's disease. Hum. Molec. Genet. 12: 2457-2466,
2003.

97. Scott, W. K.; Stajich, J. M.; Yamaoka, L. H.; Speer, M. C.; Vance,
J. M.; Roses, A. D.; Pericak-Vance, M. A.; Deane Laboratory Parkinson
Disease Research Group: Genetic complexity and Parkinson's disease.
(Letter) Science 277: 387-388, 1997.

98. Scott, W. K.; Yamaoka, L. H.; Stajich, J. M.; Scott, B. L.; Vance,
J. M.; Roses, A. D.; Pericak-Vance, M. A.; Watts, R. L.; Nance, M.;
Hubble, J.; Koller, W.; Stern, M. B.; and 15 others: The alpha-synuclein
gene is not a major risk factor in familial Parkinson disease. (Letter) Neurogenetics 2:
191-192, 1999.

99. Seidel, K.; Schols, L.; Nuber, S.; Petrasch-Parwez, E.; Gierga,
K.; Wszolek, Z.; Dickson, D.; Gai, W. P.; Bornemann, A.; Riess, O.;
Rami, A.; Den Dunnen, W. F. A.; Deller, T.; Rub, U.; Kruger, R.:
First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann.
Neurol. 67: 684-689, 2010. Note: Erratum: Ann. Neurol. 67: 841 only,
2010.

100. Sharon, R.; Bar-Joseph, I.; Frosch, M. P.; Walsh, D. M.; Hamilton,
J. A.; Selkoe, D. J.: The formation of highly soluble oligomers of
alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's
disease. Neuron 37: 583-595, 2003.

101. Shibasaki, Y.; Baillie, D. A. M.; St. Clair, D.; Brookes, A.
J.: High-resolution mapping of SNCA encoding a-synuclein, the non-A-beta
component of Alzheimer's disease amyloid precursor, to human chromosome
4q21.3-q22 by fluorescence in situ hybridization. Cytogenet. Cell
Genet. 71: 54-55, 1995.

102. Shimura, H.; Schlossmacher, M. G.; Hattori, N.; Frosch, M. P.;
Trockenbacher, A.; Schneider, R.; Mizuno, Y.; Kosik, K. S.; Selkoe,
D. J.: Ubiquitination of a new form of alpha-synuclein by parkin
from human brain: implications for Parkinson's disease. Science 293:
263-269, 2001.

103. Singleton, A. B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague,
S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum,
R.; Lincoln, S.; Crawley, A.; and 10 others: Alpha-synuclein locus
triplication causes Parkinson's disease. Science 302: 841 only,
2003.

104. Smith, W. W.; Jiang, H.; Pei, Z.; Tanaka, Y.; Morita, H.; Sawa,
A.; Dawson, V. L.; Dawson, T. M.; Ross, C. A.: Endoplasmic reticulum
stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced
toxicity. Hum. Molec. Genet. 14: 3801-3811, 2005.

105. Smith, W. W.; Liu, Z.; Liang, Y.; Masuda, N.; Swing, D. A.; Jenkins,
N. A.; Copeland, N. G.; Troncoso, J. C.; Pletnikov, M.; Dawson, T.
M.; Martin, L. J.; Moran, T. H.; Lee, M. K.; Borchelt, D. R.; Ross,
C. A.: Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein
transgenic mouse model. Hum. Molec. Genet. 19: 2087-2098, 2010.

106. Sode, K.; Usuzaka, E.; Kobayashi, N.; Ochiai, S.: Engineered
alpha-synuclein prevents wild type and familial Parkin variant fibril
formation. Biochem. Biophys. Res. Commun. 335: 432-436, 2005.

107. Spillantini, M. G.; Divane, A.; Goedert, M.: Assignment of human
alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes
4q21 and 5q35. Genomics 27: 379-381, 1995.

108. Spillantini, M. G.; Schmidt, M. L.; Lee, V. M.-Y.; Trojanowski,
J. Q.; Jakes, R.; Goedert, M.: Alpha-synuclein in Lewy bodies. Nature 388:
839-840, 1997.

109. Spira, P. J.; Sharpe, D. M.; Halliday, G.; Cavanagh, J.; Nicholson,
G. A.: Clinical and pathological features of a Parkinsonian syndrome
in a family with an ala53-to-thr alpha-synuclein mutation. Ann. Neurol. 49:
313-319, 2001.

110. Tabrizi, S. J.; Orth, M.; Wilkinson, J. M.; Taanman, J.-W.; Warner,
T. T.; Cooper, J. M.; Schapira, A. H. V.: Expression of mutant alpha-synuclein
causes increased susceptibility to dopamine toxicity. Hum. Molec.
Genet. 9: 2683-2689, 2000.

111. Tanaka, Y.; Engelender, S.; Igarashi, S.; Rao, R. K.; Wanner,
T.; Tanzi, R. E.; Sawa, A.; Dawson, V. L.; Dawson, T. M.; Ross, C.
A.: Inducible expression of mutant alpha-synuclein decreases proteasome
activity and increases sensitivity to mitochondria-dependent apoptosis. Hum.
Molec. Genet. 10: 919-926, 2001.

112. Tardiff, D. F.; Jui, N. T.; Khurana, V.; Tambe, M. A.; Thompson,
M. L.; Chung, C. Y.; Kamadurai, H. B.; Kim, H. T.; Lancaster, A. K.;
Caldwell, K. A.; Caldwell, G. A.; Rochet, J.-C.; Buchwald, S. L.;
Lindquist, S.: Yeast reveal a 'druggable' Rsp5/Nedd4 network that
ameliorates alpha-synuclein toxicity in neurons. Science 342: 979-983,
2013.

113. Touchman, J. W.; Dehejia, A.; Chiba-Falek, O.; Cabin, D. E.;
Schwartz, J. R.; Orrison, B. M.; Polymeropoulos, M. H.; Nussbaum,
R. L.: Human and mouse alpha-synuclein genes: comparative genomic
sequence analysis and identification of a novel gene regulatory element. Genome
Res. 11: 78-86, 2001.

114. Troiano, A. R.; Cazeneuve, C.; Le Ber, I.; Bonnet, A.-M.; Lesage,
S.; Brice, A.: Alpha-synuclein gene duplication is present in sporadic
Parkinson disease. Neurology 71: 1295 only, 2008.

115. Uchiyama, T.; Ikeuchi, T.; Ouchi, Y.; Sakamoto, M.; Kasuga, K.;
Shiga, A.; Suzuki, M.; Ito, M.; Atsumi, T.; Shimizu, T.; Ohashi, T.
: Prominent psychiatric symptoms and glucose hypometabolism in a family
with a SNCA duplication. Neurology 71: 1289-1290, 2008.

116. Ueda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto,
M.; Otero, D. A. C.; Kondo, J.; Ihara, Y.; Saitoh, T.: Molecular
cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer
disease. Proc. Nat. Acad. Sci. 90: 11282-11286, 1993.

117. Vaughan, J. R.; Farrer, M. J.; Wszolek, Z. K.; Gasser, T.; Durr,
A.; Agid, Y.; Bonifati, V.; DeMichele, G.; Volpe, G.; Lincoln, S.;
Breteler, M.; Meco, G.; Brice, A.; Marsden, C. D.; Hardy, J.; Wood,
N. W.; European Consortium on Genetic Susceptibility in Parkinson's
Disease (GSPD): Sequencing of the alpha-synuclein gene in a large
series of cases of familial Parkinson's disease fails to reveal any
further mutations. Hum. Molec. Genet. 7: 751-753, 1998.

118. Voutsinas, G. E.; Stavrou, E. F.; Karousos, G.; Dasoula, A.;
Papachatzopoulou, A.; Syrrou, M.; Verkerk, A. J. M. H.; van der Spek,
P.; Patrinos, G. P.; Stoger, R.; Athanassiadou, A.: Allelic imbalance
of expression and epigenetic regulation within the alpha-synuclein
wild-type and p.Ala53Thr alleles in Parkinson disease. Hum. Mutat. 31:
685-691, 2010.

119. Waters, C. H.; Miller, C. A.: Autosomal dominant Lewy body parkinsonism
in a four-generation family. Ann. Neurol. 35: 59-64, 1994.

120. Willingham, S.; Outeiro, T. F.; DeVit, M. J.; Lindquist, S. L.;
Muchowski, P. J.: Yeast genes that enhance the toxicity of a mutant
huntingtin fragment or alpha-synuclein. Science 302: 1769-1772,
2003.

121. Xu, J.; Kao, S.-Y.; Lee, F. J. S.; Song, W.; Jin, L.-W.; Yankner,
B. A.: Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism
for selective neurodegeneration in Parkinson disease. Nature Med. 8:
600-606, 2002.

122. Zarranz, J. J.; Alegre, J.; Gomez-Esteban, J. C.; Lezcano, E.;
Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atares,
B.; Llorens, V.; Gomez Tortosa, E.; del Ser, T.; Munoz, D. G.; de
Yebenes, J. G.: The new mutation, E46K, of alpha-synuclein causes
parkinson and Lewy body dementia. Ann. Neurol. 55: 164-173, 2004.

*FIELD* CN
Cassandra L. Kniffin - updated: 2/3/2014
Ada Hamosh - updated: 12/6/2013
George E. Tiller - updated: 8/15/2013
Cassandra L. Kniffin - updated: 3/4/2013
Ada Hamosh - updated: 1/7/2013
Patricia A. Hartz - updated: 2/28/2012
Patricia A. Hartz - updated: 1/11/2012
George E. Tiller - updated: 12/2/2011
George E. Tiller - updated: 11/17/2011
Cassandra L. Kniffin - updated: 11/14/2011
Ada Hamosh - updated: 9/27/2011
Patricia A. Hartz - updated: 2/4/2011
Ada Hamosh - updated: 11/10/2010
Cassandra L. Kniffin - updated: 10/25/2010
Patricia A. Hartz - updated: 8/4/2010
George E. Tiller - updated: 7/21/2010
Cassandra L. Kniffin - updated: 6/17/2010
Patricia A. Hartz - updated: 1/11/2010
George E. Tiller - updated: 8/12/2009
George E. Tiller - updated: 7/6/2009
Cassandra L. Kniffin - updated: 5/29/2009
Cassandra L. Kniffin - updated: 4/24/2009
Cassandra L. Kniffin - updated: 3/27/2009
Cassandra L. Kniffin - updated: 3/17/2009
Cassandra L. Kniffin - updated: 1/9/2009
Cassandra L. Kniffin - updated: 10/28/2008
George E. Tiller - updated: 4/29/2008
Cassandra L. Kniffin - updated: 3/18/2008
Cassandra L. Kniffin - updated: 1/7/2008
Cassandra L. Kniffin - updated: 12/18/2007
Ada Hamosh - updated: 8/17/2007
Cassandra L. Kniffin - updated: 6/12/2007
Cassandra L. Kniffin - updated: 2/20/2007
Ada Hamosh - updated: 11/28/2006
Cassandra L. Kniffin - updated: 11/6/2006
Cassandra L. Kniffin - updated: 4/20/2006
Cassandra L. Kniffin - updated: 12/20/2005
Cassandra L. Kniffin - updated: 10/19/2005
George E. Tiller - updated: 9/12/2005
Cassandra L. Kniffin - updated: 7/19/2005
Cassandra L. Kniffin - updated: 6/13/2005
Victor A. McKusick - updated: 3/10/2005
Cassandra L. Kniffin - updated: 2/10/2005
Ada Hamosh - updated: 10/5/2004
Anne M. Stumpf - updated: 6/17/2004
Cassandra L. Kniffin - updated: 6/4/2004
Ada Hamosh - updated: 12/30/2003
George E. Tiller - updated: 12/3/2003
Cassandra L. Kniffin - updated: 11/10/2003
Cassandra L. Kniffin - updated: 7/11/2003
Victor A. McKusick - updated: 6/6/2003
Cassandra L. Kniffin - updated: 4/29/2003
Victor A. McKusick - updated: 3/28/2003
Patricia A. Hartz - updated: 3/10/2003
Cassandra L. Kniffin - updated: 2/19/2003
Victor A. McKusick - updated: 12/17/2002
Cassandra L. Kniffin - updated: 9/6/2002
Victor A. McKusick - updated: 8/26/2002
Ada Hamosh - updated: 7/25/2002
Ada Hamosh - updated: 7/24/2002
Ada Hamosh - updated: 2/6/2002
Victor A. McKusick - updated: 10/29/2001
George E. Tiller - updated: 10/1/2001
Ada Hamosh - updated: 8/13/2001
George E. Tiller - updated: 1/25/2001
Ada Hamosh - updated: 11/14/2000
Ada Hamosh - updated: 3/27/2000
Ada Hamosh - updated: 3/2/2000
Victor A. McKusick - updated: 2/9/2000
Victor A. McKusick - updated: 1/12/2000
Victor A. McKusick - updated: 12/16/1999
Victor A. McKusick - updated: 6/21/1999
Victor A. McKusick - updated: 4/22/1999
Victor A. McKusick - updated: 2/2/1999
Jennifer P. Macke - updated: 5/9/1998
Victor A. McKusick - updated: 5/5/1998
Orest Hurko - updated: 4/7/1998
Victor A. McKusick - updated: 1/23/1998
Victor A. McKusick - updated: 8/1/1997
Victor A. McKusick - updated: 6/27/1997

*FIELD* CD
Victor A. McKusick: 12/14/1993

*FIELD* ED
carol: 02/06/2014
mcolton: 2/4/2014
ckniffin: 2/3/2014
alopez: 12/6/2013
carol: 8/16/2013
tpirozzi: 8/16/2013
tpirozzi: 8/15/2013
terry: 4/4/2013
carol: 3/8/2013
ckniffin: 3/4/2013
alopez: 1/7/2013
terry: 1/7/2013
terry: 11/29/2012
mgross: 6/5/2012
terry: 2/28/2012
mgross: 2/24/2012
terry: 1/11/2012
alopez: 12/2/2011
terry: 12/2/2011
carol: 11/22/2011
terry: 11/17/2011
carol: 11/16/2011
terry: 11/16/2011
ckniffin: 11/14/2011
terry: 10/13/2011
alopez: 10/5/2011
terry: 9/27/2011
mgross: 4/12/2011
terry: 2/4/2011
terry: 1/21/2011
ckniffin: 11/17/2010
alopez: 11/15/2010
terry: 11/10/2010
wwang: 11/1/2010
ckniffin: 10/25/2010
wwang: 8/4/2010
wwang: 7/26/2010
wwang: 7/21/2010
ckniffin: 6/17/2010
mgross: 1/11/2010
carol: 11/6/2009
ckniffin: 11/5/2009
wwang: 8/25/2009
terry: 8/12/2009
alopez: 7/7/2009
terry: 7/6/2009
carol: 6/23/2009
wwang: 6/4/2009
ckniffin: 5/29/2009
wwang: 5/4/2009
ckniffin: 4/24/2009
wwang: 4/7/2009
ckniffin: 3/27/2009
wwang: 3/26/2009
ckniffin: 3/17/2009
wwang: 1/15/2009
ckniffin: 1/9/2009
carol: 12/23/2008
wwang: 11/7/2008
ckniffin: 10/28/2008
wwang: 5/1/2008
terry: 4/29/2008
wwang: 4/15/2008
ckniffin: 3/19/2008
ckniffin: 3/18/2008
carol: 2/29/2008
wwang: 1/23/2008
ckniffin: 1/7/2008
wwang: 1/7/2008
ckniffin: 12/18/2007
carol: 8/17/2007
ckniffin: 6/12/2007
wwang: 2/22/2007
ckniffin: 2/20/2007
alopez: 12/7/2006
terry: 11/28/2006
wwang: 11/9/2006
ckniffin: 11/6/2006
alopez: 8/22/2006
wwang: 4/26/2006
ckniffin: 4/20/2006
wwang: 12/27/2005
ckniffin: 12/20/2005
carol: 10/20/2005
ckniffin: 10/19/2005
alopez: 10/18/2005
terry: 9/12/2005
wwang: 7/26/2005
ckniffin: 7/19/2005
wwang: 6/16/2005
ckniffin: 6/13/2005
wwang: 3/23/2005
wwang: 3/15/2005
terry: 3/10/2005
terry: 2/22/2005
tkritzer: 2/22/2005
ckniffin: 2/10/2005
terry: 11/2/2004
tkritzer: 10/6/2004
terry: 10/5/2004
alopez: 6/17/2004
tkritzer: 6/11/2004
ckniffin: 6/4/2004
alopez: 12/30/2003
terry: 12/30/2003
mgross: 12/3/2003
carol: 11/11/2003
ckniffin: 11/10/2003
carol: 7/11/2003
ckniffin: 7/11/2003
carol: 6/19/2003
tkritzer: 6/17/2003
terry: 6/6/2003
ckniffin: 5/28/2003
tkritzer: 4/29/2003
ckniffin: 4/29/2003
cwells: 4/3/2003
terry: 3/28/2003
mgross: 3/12/2003
terry: 3/10/2003
carol: 2/24/2003
ckniffin: 2/19/2003
tkritzer: 12/18/2002
tkritzer: 12/17/2002
carol: 12/16/2002
tkritzer: 12/12/2002
ckniffin: 12/9/2002
carol: 10/29/2002
carol: 9/10/2002
ckniffin: 9/6/2002
tkritzer: 9/6/2002
tkritzer: 8/28/2002
terry: 8/26/2002
cwells: 7/26/2002
terry: 7/25/2002
terry: 7/24/2002
alopez: 2/7/2002
terry: 2/6/2002
carol: 11/1/2001
mcapotos: 11/1/2001
terry: 10/29/2001
cwells: 10/9/2001
cwells: 10/1/2001
alopez: 8/14/2001
terry: 8/13/2001
mcapotos: 2/1/2001
mcapotos: 1/25/2001
mgross: 11/16/2000
terry: 11/14/2000
alopez: 3/30/2000
terry: 3/27/2000
alopez: 3/2/2000
mgross: 3/1/2000
terry: 2/9/2000
mgross: 2/7/2000
terry: 1/12/2000
mgross: 1/10/2000
terry: 12/16/1999
alopez: 6/21/1999
mgross: 5/5/1999
mgross: 4/27/1999
terry: 4/22/1999
carol: 2/15/1999
terry: 2/2/1999
carol: 8/24/1998
terry: 6/3/1998
alopez: 5/9/1998
carol: 5/5/1998
terry: 4/7/1998
mark: 1/26/1998
terry: 1/23/1998
terry: 8/5/1997
terry: 8/1/1997
mark: 6/27/1997
terry: 6/27/1997
mark: 6/20/1996
mark: 10/13/1995
mimadm: 12/2/1994
carol: 12/14/1993

MIM 168600
*RECORD*
*FIELD* NO
168600
*FIELD* TI
#168600 PARKINSON DISEASE, LATE-ONSET; PD
;;PARK
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morelate-onset or sporadic Parkinson disease (PD) can have more than one
genetic and/or environmental cause.

DESCRIPTION

Parkinson disease was first described by James Parkinson in 1817. It is
the second most common neurodegenerative disorder after Alzheimer
disease (AD; 104300), affecting approximately 1% of the population over
age 50 (Polymeropoulos et al., 1996).

- Reviews

Warner and Schapira (2003) reviewed the genetic and environmental causes
of Parkinson disease. Feany (2004) reviewed the genetics of Parkinson
disease and provided a speculative model of interactions among proteins
implicated in PD. Lees et al. (2009) provided a review of Parkinson
disease, with emphasis on diagnosis, neuropathology, and treatment.

- Genetic Heterogeneity of Parkinson Disease

Several gene loci implicated in autosomal dominant forms of Parkinson
disease have been identified, including PARK1 (168601) and PARK4, due to
mutation in or triplication of the alpha-synuclein gene (SNCA; 163890),
respectively, on 4q22.1; PARK5 (191342), due to mutation in the UCHL1
gene on 4p14; PARK8 (607060), due to mutation in the LRRK2 gene (609007)
on 12q12; PARK11 (607688), due to mutation in the GIGYF2 gene (612003)
on 2q37; and PARK13 (610297), due to mutation in the HTRA2 gene (606441)
on 2p12. PARK17 (614203) is caused by mutation in the VPS35 gene
(601501) on chromosome 16q12, and PARK18 (614251) is caused by mutation
in the EIF4G1 gene (600495) on chromosome 3q27.

Several loci for autosomal recessive early-onset Parkinson disease have
been identified: PARK2 (600116), caused by mutation in the gene encoding
parkin (PARK2; 602544) on 6q25.2-q27; PARK6 (605909), caused by mutation
in the PINK1 gene (608309) on 1p36; PARK7 (606324), caused by mutation
in the DJ1 gene (PARK7; 602533) on 1p36; PARK14 (612953), caused by
mutation in the PLA2G6 gene (603604) on 22q13; PARK15 (260300), caused
by mutation in the FBXO7 gene (605648) on 22q12-q13; PARK19 (615528),
caused by mutation in the DNAJC6 gene (608375) on 1p32; and PARK20
(615530), caused by mutation in the SYNJ1 gene (604297) on 21q22.

PARK3 (602404) has been mapped to chromosome 2p13; PARK10 (606852) has
been mapped to chromosome 1p34-p32; PARK16 (613164) has been mapped to
chromosome 1q32. A locus on the X chromosome has been identified
(PARK12; 300557). There is also evidence that mitochondrial mutations
may cause or contribute to Parkinson disease (see 556500).

Susceptibility to the development of the more common late-onset form of
Parkinson disease has been associated with polymorphisms or mutations in
several genes, including GBA (606463), MAPT (157140), MC1R (155555),
ADH1C (103730), and genes at the HLA locus (see, e.g., HLA-DRA, 142860).
Each of these risk factors independently may have a modest effect on
disease development, but together may have a substantial cumulative
effect (Hamza et al., 2010).

Susceptibility to PD may also be conferred by expanded trinucleotide
repeats in several genes causing other neurologic disorders usually
characterized by spinocerebellar ataxia (SCA), including the ATXN2
(601517), ATXN3 (607047), TBP (600075), and ATXN8OS (603680) genes.

CLINICAL FEATURES

The diagnosis of classic idiopathic PD is primarily clinical, with
manifestations including resting tremor, muscular rigidity,
bradykinesia, and postural instability. Additional features are
characteristic postural abnormalities, dysautonomia, dystonic cramps,
and dementia. The disease is progressive and usually has an insidious
onset in mid to late adulthood. Pathologic features of classic PD
include by a loss of dopaminergic neurons in the substantia nigra (SN)
and the presence of Lewy bodies, intracellular inclusions, in surviving
neurons in various areas of the brain, particularly the SN (Nussbaum and
Polymeropoulos, 1997). Autosomal recessive juvenile Parkinson disease
(PARK2; 600116), however, does not have Lewy body pathology (Nussbaum
and Polymeropoulos, 1997).

Many other diseases, both genetic and nongenetic, have parkinsonian
motor features ('parkinsonism'), which most likely result from loss or
dysfunction of the dopaminergic neurons in the SN, but may or may not
have Lewy bodies on pathology. Thus, accurate diagnosis may be difficult
without pathologic examination. Dementia with Lewy bodies (DLB; 127750)
shows parkinsonism with Lewy bodies. However, parkinsonism without Lewy
bodies characterizes progressive supranuclear palsy (PSP; 601104),
frontotemporal dementia with parkinsonism (600274), autosomal dominant
(128230) and recessive (605407) forms of Segawa syndrome, X-linked
recessive Filipino type of dystonia (314250), multiple systems atrophy,
and cerebrovascular disease.

OTHER FEATURES

In a retrospective analysis, Paleacu et al. (2005) found that 76 (32%)
of 234 PD patients reported hallucinations. All experienced visual
hallucinations, most commonly of human images, and 6 also reported mood
congruent auditory hallucinations. The presence of hallucinations was
correlated with family history of dementia and lower scores on the
Mini-Mental State Examination (MMSE). Neither the dose nor duration of
L-dopa treatment was a significant variable for hallucinations.

Using PET scan, Ballanger et al. (2010) showed that 7 PD patients with
visual hallucinations had increased binding to serotonin 2A receptors
(HTR2A; 182135) in the ventral visual pathway compared to 7 PD patients
without visual hallucinations. Areas of the ventral visual pathway that
showed increased HTR2A binding included the bilateral inferooccipital
gyrus, the right fusiform gyrus, and the inferotemporal cortex. The
findings suggested that abnormalities in serotonin 2A receptor
neurotransmission may be involved in the pathogenesis of visual
hallucinations in PD.

Using single-photon emission CT with a radiolabeled ligand for several
beta-2 (CHRNB2; 118507)-containing nicotinic acetylcholine receptors
(nAChR), Fujita et al. (2006) showed that 10 nondemented PD patients had
a widespread significant global decrease in nAChRs compared to 15
controls. The most significant decrease was in the thalamus.

Some studies have observed an increased risk of Parkinson disease among
individuals with melanoma (155600) (see, e.g., Constantinescu et al.,
2007 and Ferreira et al., 2007), suggesting that pigmentation metabolism
may be involved in the pathogenesis of PD. From 2 existing study cohorts
of 38,641 men and 93,661 women who were free of PD at baseline, Gao et
al. (2009) found an association between decreasing darkness of natural
hair color in early adulthood and increased PD risk. The pooled relative
risks (RR) for PD were 1.0 (reference risk), 1.40, 1.61, and 1.93 for
black, brown, blond, and red hair, respectively. These results were
significant after adjusting for age, smoking, ethnicity, and other
covariates. The associations between hair color and PD were particularly
strong for onset before age 70 years. In a case-control study of 272 PD
cases and 1,185 controls, there was an association between the cys151
SNP of the MCR1 gene (155555.0004), which confers red hair, and
increased risk of PD relative to the arg151 SNP (relative risk of 3.15
for the cys/cys genotype). Noting that melanin, like dopamine, is
synthesized from tyrosine, and that PD is characterized by the loss of
neuromelanin-containing neurons in the substantia nigra, Gao et al.
(2009) postulated a link between pigmentation and development of PD.
Hernandez (2009) independently noted the association.

In a study of 157,036 individuals, who did not have PD at baseline, over
a 14 to 20-year follow-up period, Gao et al. (2009) identified 616
incident PD cases. A family history of melanoma in a first-degree
relative was associated with a higher risk of PD (RR, 1.85; p = 0.004)
after adjusting for smoking, ethnicity, caffeine intake, and other
covariates. There was no association between a family history of
colorectal, lung, prostate, or breast cancer and PD risk. The findings
supported the notion that melanoma and Parkinson disease share common
genetic components.

INHERITANCE

There has been much controversy regarding the genetics of Parkinson
disease, as no specific pattern of inheritance is readily apparent, and
reports of Parkinson disease and parkinsonism may not necessarily refer
to the same disease entity (Nussbaum and Polymeropoulos, 1997). However,
a familial component to Parkinson disease and parkinsonism has long been
recognized.

Gowers (1900) is believed to have been the first to observe that
patients with PD often had an affected relative, and he suggested that
hereditary factors may be important. Bell and Clark (1926) reviewed
published pedigrees of 'paralysis agitans' and reported an additional
one. Allan (1937) described impressive pedigrees from North Carolina.

- Twin Studies

Kissel and Andre (1976) described a pair of female MZ twins, both of
whom had a combination of parkinsonism and anosmia. Olfactory impairment
is frequent in PD (Ward et al., 1983). Both twins reported onset of
symptoms at age 36 years, which is unusually early, particularly for
women (Kessler, 1978). Kissel and Andre (1976) noted that 2 families
with the same association had previously been reported and they
suggested a causative role for a genetically determined anomaly of
dopamine metabolism.

Duvoisin et al. (1981) found zero concordance for Parkinson disease in
the first 12 monozygotic twin pairs examined in an on-going twin study.
There was evidence of premorbid personality differences between probands
and cotwins dating back to late adolescence or early adult years. Among
43 monozygotic and 19 dizygotic twin pairs, Ward et al. (1983) found
that only 1 monozygotic twin pair was definitely concordant for PD. Ward
et al. (1983) noted that concordance for PD is no more frequent in twins
than would be expected from the incidence of the disease, and concluded
that major factors in the etiology of PD must be nongenetic.

- Mendelian Inheritance

Spellman (1962) described a family in which multiple members in 4
generations had parkinsonism beginning in their thirties and progressing
rapidly to death in 2 to 12 years. Tune et al. (1982) described
Parkinson disease in 4 persons in 3 generations. Several of these also
had manic-depressive illness.

Barbeau and Pourcher (1982, 1983) suggested that mendelian inheritance
obtains in some cases, particularly in those whose illness started
before the age of 40. In this early-onset group, there was a 46%
incidence of familial cases. They divided Parkinson disease into 4
etiologic categories: postencephalitic, idiopathic, genetic, and
symptomatic. They proposed the existence of 2 genetic subtypes: an
akineto-rigid subtype transmitted as an autosomal recessive and a
subtype with prominent tremor, dominant inheritance, and a high
prevalence of family members with essential tremor.

Lazzarini et al. (1994) found that the cumulative risk of PD among sibs
of probands with affected parents was increased significantly over that
for sibs of probands without affected parents, suggesting significant
familial aggregation in a subset of randomly ascertained families.
Furthermore, in 80 multicase families, age-adjusted ratios approaching
0.5 and similar proportions of affected parents and sibs, as well as the
distribution of ancestral secondary cases, were compatible with an
autosomal dominant mode of inheritance with reduced penetrance in a
subset of PD. Payami et al. (1995) studied age of onset of 137 patients
with idiopathic Parkinson disease. The 21 probands with an affected
parent, aunt, or uncle were younger at onset of PD (47.7 +/- 8.8 years)
than were the 11 probands with an affected sib only (60.3 +/- 12.9
years) and the 105 probands with no affected relatives (59.2 +/- 11.4
years). Age of onset of affected family members differed significantly
between generations (p = 0.0001) and was earlier, by an average of 17
years, in the proband generation than in the parental generation. The
data were consistent with genetic anticipation and suggested the
involvement of an unstable trinucleotide repeat. Markopoulou et al.
(1995) studied a Greek-American kindred with 98 individuals in 6
generations. Sixteen individuals in 3 generations developed
parkinsonism, which appeared to be transmitted in an autosomal dominant
manner with evidence of anticipation. No pathologic data were presented.

Plante-Bordeneuve et al. (1995) studied 14 families in which the proband
and at least one relative were affected by clinically typical Parkinson
disease, based on Parkinson Disease Society brain bank diagnostic
criteria (Hughes et al., 1992). No clinical differences were found
between 31 individuals with familial Parkinson disease and 31
age-matched sporadic Parkinson disease controls. In the 14 families,
genetic transmission was compatible with autosomal dominant transmission
with several cases of male-to-male transmission. Although the total
segregation ratio was 0.25, this was age-dependent, with a penetrance of
zero below age 30 and a penetrance of 0.43 over the age of 70. Age at
onset was identical within a generation but it was 26 +/- 4.6 years
earlier in children than parents of the 8 multigenerational kindreds
studied, suggesting an anticipation phenomenon.

Bonifati et al. (1995) used epidemiologic methods to determine the
frequency of clinical features of familial Parkinson disease. By
studying 100 consecutive Parkinson disease cases presenting to their
clinic, family history for Parkinson disease was positive in 24% of
Parkinson disease cases and in only 6% of spouse controls. In a larger
study of 22 nonconsecutive Parkinson disease families with at least 2
living and personally examined cases, the crude segregation ratios were
similar for parents and sibs, with lifetime cumulative risks approaching
0.4. This data supported autosomal dominant inheritance with a strong
age factor in penetrance.

Nussbaum and Polymeropoulos (1997) reviewed the genetics of Parkinson
disease. They stated that for the previous 40 years, research into
Parkinson disease had predominantly been the province of epidemiologists
interested in pursuing the connection between the disorder and
environmental factors such as viral infection or neurotoxins. Hereditary
influences were discounted because of a high discordance rate among
monozygotic twins found in studies that were later shown to be
inadequate and inconclusive. On the other hand, a positive family
history was recognized as a major risk factor for the disease and it
became increasingly apparent from neuropathologic studies that the
common, idiopathic form of Parkinson disease had a specific pathologic
correlate in the form of Lewy bodies, an eosinophilic cytoplasmic
inclusion body, distributed diffusely throughout the substantia nigra,
hypothalamus, hippocampus, autonomic ganglia, and olfactory tracts. They
referred to the 'particularly prescient paper' of Sommer and Rocca
(1996), in which the authors suggested that autosomal dominant PD may be
caused by a missense mutation in a cellular protein that changes its
physical-chemical properties, leading to accumulation of the abnormal
protein and neuronal death. This hypothesis has received substantial
support.

Maher et al. (2002) collected information involving the nuclear families
of 948 consecutively ascertained Parkinson disease index cases from 3
U.S. medical centers. They performed segregation analysis to assess
evidence for the presence of a mendelian pattern of familial
transmission. The proportion of male (60.4%) and female (39.6%) cases,
the mean age of onset (57.7 years), and the proportion of affected
fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were
similar across the 3 institutions. They concluded that the analyses
supported the presence of a rare major mendelian gene for PD in both the
age-of-onset and susceptibility model. The age-of-onset model provided
evidence for a gene that influences age-dependent penetrance of PD,
influencing age of onset rather than susceptibility. Maher et al. (2002)
also found evidence for a mendelian gene influencing susceptibility to
the disease. It was not evident whether these 2 analyses were modeling
the same gene or different genes with different effects on PD. Genes
influencing penetrance may interact with environmental factors or other
genes to increase the risk of PD. Such gene-environment interactions,
involving reduced penetrance in PD, may explain the low concordance
rates among monozygotic twins for this disorder.

In a comparison of 221 PD patients with age at onset of 50 years or
younger, 266 PD patients with age at onset of 50 years or greater, and
409 unaffected controls, Marder et al. (2003) found a similar relative
risk (RR) of PD among first-degree relatives of both the early- and
late-onset groups (RR = 2.9 and 2.7, respectively) compared to those of
controls. There was also an increased risk of PD in sibs of affected
patients (RR = 7.9 for early-onset and 3.6 for late-onset) compared to
those of controls. Parents of the early-onset group were not at a
significantly increased risk compared to those of controls (RR = 1.7),
and parents of the late-onset group were at a higher increased risk
compared to those of controls (RR = 2.5). Marder et al. (2003) concluded
that the pattern was consistent with an autosomal recessive contribution
to the inheritance of early- but not late-onset PD, but also noted that
genetic factors are important in both groups.

- 'Familial Component'

Zareparsi et al. (1998) performed complex segregation analyses using
kindreds of 136 Parkinson disease patients randomly ascertained from a
clinic population. They rejected the hypotheses of a nontransmissible
environmental factor, a major gene or type (sporadic), and all mendelian
inheritance (dominant, recessive, additive, decreasing). They concluded
that familial clustering of PD in this dataset was best explained by a
'rare familial factor' which is transmitted in a nonmendelian fashion
and influences the age at onset of PD.

Montgomery et al. (1999) used a previously reported PD test battery to
check for mild signs of motor slowing, impaired sense of smell, and
depressed mood in first-degree relatives of patients with Parkinson
disease, most of whom were considered sporadic cases. Abnormalities on
the test battery were found in 22.5% of first-degree relatives, all of
whom were judged normal on standard neurologic examination, but in only
9% of age-matched controls. The authors interpreted this familial
clustering of minimal parkinsonian tendencies as an indication of
genetic predisposition to Parkinson disease even in sporadic cases.

Sveinbjornsdottir et al. (2000) reviewed the medical records and
confirmed the diagnosis of Parkinson disease in 772 living and deceased
patients in whom the diagnosis had been made in Iceland during the
previous 50 years. With the use of an extensive computerized database
containing genealogic information on 610,920 people in Iceland over the
past 11 centuries, they conducted several analyses to determine whether
the patients were more related to each other than random members of the
population. They found that there was a genetic component to Parkinson
disease, including a subgroup of 560 patients with late-onset disease
(onset after 50 years of age): patients with Parkinson disease were
significantly more related to each other than were subjects in matched
groups of controls, and this relatedness extended beyond the nuclear
family. There was no highly penetrant mendelian pattern of inheritance,
and both early and late-onset forms often skipped generations. The risk
ratio for Parkinson disease was 6.7 for sibs, 3.2 for offspring, and 2.7
for nephews and nieces of patients with late-onset Parkinson disease.

Racette et al. (2002) described a very large Amish pedigree with classic
idiopathic Parkinson disease in multiple members. They examined 113
members and classified 67 as having no evidence of PD, 17 as clinically
definite PD, 6 as clinically probable PD, and 23 as clinically possible
PD. The mean age at onset of the clinically definite subjects was 56.7
years. The mean kinship coefficient in the subjects with PD and those
with PD by history was higher (p = 0.007) than in a group of age-matched
normal Amish control subjects, providing evidence that PD is inherited
in this family. Sequence analysis did not reveal any mutations in known
PD genes. No single haplotype cosegregated with the disease in any of
the chromosomal regions previously found to be linked to PD.

- Environmental Factors

Some findings suggest that environmental factors may be more important
than genetic factors in familial aggregation of Parkinson disease. Calne
et al. (1987) reported 6 families in which onset of symptoms tended to
occur at approximately the same time regardless of the age of the
patient. In a hospital-based survey, Teravainen et al. (1986) concluded
that there is a trend toward lower age of onset of Parkinson disease.

Calne and Langston (1983) advanced the view that in most cases the cause
is an environmental factor, possibly toxic, superimposed on a background
of slow, sustained neuronal loss due to advancing age. Finding
parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropteridine
(meperidine; MPTP) drug users (Langston et al., 1983) revived interest
in reexamining environmental factors. Barbeau et al. (1985) also
postulated that Parkinson disease is the result of environmental factors
acting on genetically susceptible persons against a background of
'normal' aging.

Nathans (2005) noted the remarkable coincidence that the abbreviation
MPTP, for the drug that causes Parkinson disease by selectively damaging
dopaminergic neurons, is coincidentally the code for the first 4 amino
acids of human, mouse, and rat tyrosine hydroxylase, the enzyme which
marks all dopaminergic neurons.

In a case-control study of 418 Chinese PD patients and 468 controls, Tan
et al. (2007) found a significant association between caffeine intake
and decreased risk of PD (p = 2.01 x 10(-5)). The odds ratio was 0.48
for moderate and high caffeine intake and 0.71 for low intake. No
difference was observed with genotyping for a common SNP in the CYP1A2
gene (124060), which influences the level of caffeine metabolism. The
findings suggested that caffeine and its main metabolite paraxanthine
are both neuroprotective.

- Multifactorial Inheritance

Analysis of the experience at the Mayo Clinic led Kondo et al. (1973) to
conclude that irregular dominant transmission is untenable and that
multifactorial inheritance with heritability of about 80% is more
likely. Young et al. (1977) favored multifactorial inheritance but could
not exclude autosomal dominance with reduced penetrance, especially for
some families. Affected relatives were bilaterally distributed more
often than would be expected for autosomal dominance.

Vaughan et al. (2001) reviewed the genetics of parkinsonism. They
suggested that nigral degeneration with Lewy body formation and the
resulting clinical picture of Parkinson disease may represent a final
common pathway of a multifactorial disease process in which both
environmental and genetic factors have a role.

Also see review of Parkinson disease by Nussbaum and Ellis (2003).

- Mitochondrial Inheritance

Another theory of parkinsonism suggests that genetic predisposition may
be transmitted through mitochondrial inheritance (Di Monte, 1991); see
556500. Schapira (1995) reviewed nuclear and mitochondrial genetics in
Parkinson disease. He stated that Gowers (1900) had noted the occurrence
of PD in relatives and suggested that hereditary factors are important.

From a study of Parkinson disease in twins, Tanner et al. (1999)
concluded that 'no genetic component was evident when the disease begins
after age 50 years.' Parker et al. (1999) and Simon (1999) pointed out
that whereas this may be true as far as mendelian (nuclear) genetic
mechanisms are concerned, this may not be true for mitochondrial factors
in Parkinson disease. Since MZ and DZ twins each receive all of their
mitochondrial DNA from their mother, differences in concordance rates
between MZ and DZ twins cannot be used to address the potential
influence of mitochondrial genetic factors.

To test the hypothesis that mitochondrial variation contributes to
Parkinson disease expression, van der Walt et al. (2003) genotyped 10
single-nucleotide polymorphisms that define the European mitochondrial
DNA haplogroups in 609 white patients with Parkinson disease and 340
unaffected white control subjects. Overall, individuals classified as
haplogroup J (odds ratio = 0.55; 95% CI 0.34-0.91; p = 0.02) or K (odds
ratio = 0.52; 95% CI 0.30-0.90; p = 0.02) demonstrated a significant
decrease in risk of Parkinson disease versus individuals carrying the
most common haplogroup H. Furthermore, a specific SNP that defines these
2 haplogroups, 10398G (516002.0002), is strongly associated with this
protective effect (odds ratio = 0.53; 95% CI 0.39-0.73; p = 0.0001). The
10398G SNP causes a nonconservative amino acid change from threonine to
alanine within the ND3 (516002) of complex I. After stratification by
sex, this decrease in risk appeared stronger in women than in men. In
addition, the 9055A SNP of ATP6 (516060) demonstrated a protective
effect for women. Van der Walt et al. (2003) concluded that ND3 is an
important factor in Parkinson disease susceptibility among white
individuals and could help explain the role of complex I in Parkinson
disease expression.

CLINICAL MANAGEMENT

Gill et al. (2003) delivered glial cell line-derived neurotrophic factor
(GDNF; 600837) directly into the putamen of 5 Parkinson patients in a
phase 1 safety trial. One catheter needed to be repositioned and there
were changes in the MRIs that disappeared after lowering the
concentration of GDNF. After 1 year, there were no serious clinical side
effects, a 39% improvement in the off-medication motor subscore of the
Unified Parkinson Disease Rating Scale (UPDRS), and a 61% improvement in
the activities of daily living subscore. Medication-induced dyskinesias
were reduced by 64% and were not observed off medication during chronic
GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine
uptake showed a significant 28% increase in putamen dopamine storage
after 18 months, suggesting a direct effect of GDNF on dopamine
function.

Voon et al. (2007) evaluated 21 patients with Parkinson disease who
developed pathologic gambling (606349) after receiving pharmacologic
treatment with dopaminergic agonists. Compared to 42 PD patients without
compulsive behaviors, those who developed pathologic gambling had a
younger age at PD onset, higher novelty seeking (601696), tended to have
medication-induced hypomania or mania, impaired planning, and a personal
or family history of alcohol use disorders (103780).

L-dopa is predominantly metabolized to the inactive 3-O-methyldopa by
COMT (116790). Entacapone is a COMT inhibitor that acts to prolong the
half-life of L-dopa and yields prolonged therapeutic benefits. A
val158-to-met (V158M) polymorphism in the COMT gene (dbSNP rs4680;
116790.0001) confers increased (val) or decreased (met) COMT activity.
In a randomized control trial of 33 PD patients, Corvol et al. (2011)
found that those homozygous for the high-activity val158 allele had
significantly increased COMT inhibition by entacapone and significantly
better bioavailability of and clinical response to L-dopa compared to
patients homozygous for the low-activity met158 allele. The findings
indicated that homozygosity for the val158 allele in PD patients
enhances the effect of entacapone on the pharmacodynamics and
pharmacokinetics of levodopa. The response to entacapone in heterozygous
patients was not studied.

Using unbiased phenotypic screens as an alternative to target-based
approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole
(NAB) that strongly and selectively protected diverse cell types from
alpha-synuclein (163890) toxicity. Three chemical genetic screens in
wildtype yeast cells established that NAB promoted endosomal transport
events dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These
same steps were perturbed by alpha-synuclein itself. Tardiff et al.
(2013) concluded that NAB identifies a druggable node in the biology of
alpha-synuclein that can correct multiple aspects of its underlying
pathology, including dysfunctional endosomal and endoplasmic
reticulum-to-Golgi-vesicle trafficking.

Chung et al. (2013) exploited mutation correction of iPS cells and
conserved proteotoxic mechanisms from yeast to humans to discover and
reverse phenotypic responses to alpha-synuclein, a key protein involved
in Parkinson disease. Chung et al. (2013) generated cortical neurons
from iPS cells of patients harboring alpha-synuclein mutations (A53T;
163890.0001), who are at high risk of developing PD dementia. Genetic
modifiers from unbiased screens in a yeast model of alpha-synuclein
toxicity led to identification of early pathogenic phenotypes in patient
neurons, including nitrosative stress, accumulation of endoplasmic
reticulum-associated degradation substrates, and ER stress. A small
molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin
ligase that it affects, reversed pathologic phenotypes in these neurons.

MAPPING

- Evidence for Genetic Heterogeneity

Polymeropoulos et al. (1996) demonstrated genetic linkage between an
autosomal dominant form of PD and genetic markers on 4q21-q23. The locus
was designated PARK1 (168601). In 94 Caucasian families, Scott et al.
(1997) could not demonstrate linkage to 4q21-q23. They also found no
linkage even when the 22 families from their study with at least 1 case
of early-onset PD were examined separately. Gasser et al. (1997)
excluded linkage in 13 multigenerational families with Parkinson
disease, with the exception of 1 family for which they achieved a
maximum multipoint lod score of 1.5 for genetic markers in the 4q21-q23
region.

Scott et al. (2001) described a genetic linkage study conducted in
1995-2000 in which a complete genomic screen was performed in 174
families with multiple individuals diagnosed as having idiopathic PD,
identified through probands in 13 clinic populations in the continental
United States and Australia. Significant evidence for linkage was found
in 5 distinct chromosomal regions: chromosome 6 in the parkin gene
(PARK2; 602544) in families with at least 1 individual with PD onset at
younger than 40 years (lod = 5.47); chromosomes 17q (lod = 2.62), 8p
(lod = 2.22), and 5q (lod = 1.50) overall and in families with
late-onset PD; and 9q (lod = 2.59) in families with both
levodopa-responsive and levodopa-nonresponsive patients. The data
suggested that the parkin gene is important in early-onset PD and that
multiple genetic factors may be important in the development of
idiopathic, late-onset PD.

Pankratz et al. (2002) studied 160 multiplex families with PD in which
there was no evidence of mutations in the parkin gene, and used
multipoint nonparametric linkage analysis to identify PD susceptibility
genes. For those individuals with a more stringent diagnosis of verified
PD, the highest lod scores were observed on the X chromosome and on
chromosome 2 (lod scores equal to 2.1 and 1.9, respectively). Analyses
performed with all available sib pairs, i.e., all examined individuals
treated as affected regardless of their final diagnostic classification,
yielded even greater evidence of linkage to the X chromosome and to
chromosome 2 (lod scores equal to 2.7 and 2.5, respectively). Evidence
of linkage was also found to chromosomes 4, 5, and 13 (lod scores
greater than 1.5). Pankratz et al. (2002) considered their findings
consistent with those of other linkage studies that had reported linkage
to chromosomes X and 5.

Pankratz et al. (2003) studied 754 affected individuals, comprising 425
sib pairs, to identify PD susceptibility genes. Genomewide,
nonparametric linkage analyses revealed potential loci on chromosomes 2,
X, 10, and 14. The authors hypothesized that gene-by-gene interactions
are important in PD susceptibility.

- Associations Pending Confirmation

Maraganore et al. (2005) performed a 2-tiered, genomewide association
study of PD including 443 sib pairs discordant for PD and 332
case-unrelated control pairs. A SNP (dbSNP rs7702187) within the
semaphorin-5A gene (SEMA5A; 609297) on chromosome 5p had the lowest
combined p value (p = 7.62 x 10(-6)). The protein encoded by this gene
plays an important role in neurogenesis and in neuronal apoptosis, which
was consistent with hypotheses regarding PD pathogenesis.

Gao et al. (2009) conducted a genomewide linkage screen of 5,824 SNPs in
278 families of European non-Hispanic descent to localize regions that
harbor susceptibility loci for Parkinson disease. These 278 families
included 158 families included in a previous screen (Scott et al., 2001)
and 120 families not previously screened. In the overall screen of all
278 families, the highest multipoint MLOD scores were obtained under a
dominant model of inheritance in an 11-cM interval on chromosome 3q25
(MLOD = 2.0) and a 9-cM interval on chromosome 18q11 (MLOD = 1.8). Since
the combined screen did not detect linkage overall in regions previously
implicated, Gao et al. (2009) suspected that clinical and locus
heterogeneity might exist. They stratified the dataset into previously
screened and unscreened families. In the 120 families not previously
screened, Gao et al. (2009) achieved significant evidence for linkage on
chromosome 18q11 (maximum lod score = 4.1) and suggestive evidence on
chromosome 3q25 (maximum lod score = 2.5). There was little evidence for
linkage to these regions overall in the original 158 families.
Simulation studies suggested that these findings were likely due to
locus heterogeneity rather than random statistical error. See also
PARK18 (614251), which is caused by mutation in the EIF4G1 gene (600495)
on 3q27.

To identify susceptibility variants for Parkinson disease, Satake et al.
(2009) performed a genomewide association study and 2 replication
studies in a total of 2,011 cases and 18,381 controls from Japan. They
identified a novel susceptibility locus on chromosome 4p15. Four SNPs
(dbSNP rs11931532, dbSNP rs12645693, dbSNP rs4698412, and dbSNP
rs4538475) reached p less than 5 x 10(-7) in the combined analysis. The
4 SNPs were located 4.1 kb downstream of intron 8 of the BST1 gene
(600387). Satake et al. (2009) also identified a locus on chromosome
1q32 (PARK16; 613164), replicated by Simon-Sanchez et al. (2009), and
replicated associations on 4q22 (see PARK1, 168601) and 12q12 (see
PARK8, 607060). Tan et al. (2010) confirmed associations at the PARK16,
PARK1, and PARK8 loci in 433 PD patients and 916 controls, all of
Chinese ethnicity. However, they did not identify a significant
association at the BST1 locus.

By a genomewide association study of 2,000 individuals with late-onset
PD and 1,986 unaffected controls, all of European ancestry from the
NeuroGenetics Research Consortium (NGRC), Hamza et al. (2010) found an
association between PD and dbSNP rs11248051 in the GAK gene (602052) on
chromosome 4p (p = 3.1 x 10(-4); odds ratio (OR) of 1.32). When combined
with data from a previous study (Pankratz et al., 2009), metaanalysis of
the combined dataset of 2,843 patients yielded a significant association
(p = 3.2 x 10(-9); OR, 1.46). Hamza et al. (2010) designated this
possible locus PARK17, but that symbol has been used for a confirmed PD
locus on chromosome 16q13 (see 614203). They also found a significant
association between PD and dbSNP rs3129882 in intron 1 of the HLA-DRA
(142860) gene on chromosome 6p21.3 (p = 2.9 x 10(-8)). The authors
designated this possible locus PARK18, but that symbol has been used for
a confirmed PD locus on chromosome 3q27 (see 614251). The association
was significant even after adjusting for age, sex, and genetic
substructure among Americans of European descent (as defined by Jewish
ancestry and country of origin). The findings were replicated in 2
datasets comprising 1,447 patients, and metaanalysis of the 3
populations showed a combined p value of 1.9 x 10(-10) and odds ratio of
1.26. The HLA association was uniform across all genetic and
environmental risk strata, and was strong in both sporadic (p = 5.5 x
10(-10)) and late-onset (p = 2.4 x (10-8)) disease. A data repository of
expression QTL indicated that dbSNP rs3129882 is a cis-acting regulatory
variant that correlated significantly with expression levels of HLA-DRA,
HLA-DQA2 (613503), and HLA-DRB5 (604776). Hamza et al. (2010) suggested
that their findings supported the involvement of the immune system in
the pathogenesis of Parkinson disease. However, Mata et al. (2011)
failed to replicate the associations between Parkinson disease and the
loci at chromosome 4p and 6p21 in a study of 1,445 PD patients and 1,161
controls from northern Spain. The SNPs studied included dbSNP rs11248051
in the GAK gene and dbSNP rs3129882 in the HLA-DRA gene. Mata et al.
(2011) concluded that the loci designated PARK17 and PARK18 by Hamza et
al. (2010) required further validation.

MOLECULAR GENETICS

Investigating the postulate that PD may have an environmental cause,
Barbeau et al. (1985) noted that many potential neurotoxic xenobiotics
are detoxified by hepatic cytochrome P450. They studied one such system
in 40 patients with Parkinson disease and 40 controls, and found that
significantly more patients than controls had partially or totally
defective 4-hydroxylation of debrisoquine (608902). Poor metabolizers
had earlier onset of disease. Bordet et al. (1994) investigated a
genetic polymorphism of the cytochrome P450 CYP2D6 gene (124030) in 105
patients with idiopathic Parkinson disease and 15 patients with diffuse
Lewy body disease. They found no relationship between the CYP2D6 gene
associated with poor metabolism of debrisoquine with either idiopathic
Parkinson disease or diffuse Lewy body disease. Sandy et al. (1996)
found no significant differences in CYP2D6 allelic frequencies between
early-onset Parkinson disease cases (51 years of age or less) and
controls.

Kurth et al. (1993) found a single-strand conformation polymorphism in
intron 13 of the monoamine oxidase B gene (309860) and found a
significantly higher frequency of 1 allele in their parkinsonian
population compared with the control group. Ho et al. (1995), however,
were unable to substantiate this claim.

Parboosingh et al. (1995) failed to find pathogenic mutations in either
copper/zinc (147450) or manganese (147460) superoxide dismutase or in
catalase (115500) in a single-strand conformation analysis of 107
unrelated patients with Parkinson disease, which included both familial
and sporadic cases.

Polymeropoulos (1997) noted that Polymeropoulos et al. (1997) had
reported a total of 4 families in which mutation in the alpha-synuclein
gene (SNCA; 163890) could be shown to be responsible for early-onset
Parkinson disease. However, mutation was not detected in 50 individuals
with sporadic Parkinson disease or in 2 other families with late onset
of the illness.

Wu et al. (2001) analyzed 224 Taiwanese patients with PD for MAOB intron
13 G (309860) and COMT L (V158M; 116790.0001) polymorphisms and found
that the MAOB G genotype (G in men, G/G in women) was associated with a
2.07-fold increased relative risk for PD, an association which was
stronger for men than for women. Although COMT polymorphism alone was
not associated with an increased risk for PD, when it was considered in
conjunction with the MAOB G genotype, there was a 2.4-fold increased
relative risk for PD. In men, the combined alleles, MAOB G and COMT L,
increased the relative risk for PD to 7.24. Wu et al. (2001) suggested
that, in Taiwanese, the development of PD may be related to the
interaction of 2 or more genes involved in dopamine metabolism.

The demonstration of linkage of idiopathic Parkinson disease to 17q21
(Scott et al., 2001) made the tau gene (MAPT; 157140) a good candidate
as a susceptibility gene for idiopathic PD. Martin et al. (2001) tested
5 single-nucleotide polymorphisms (SNPs) within the MAPT gene for
association with PD in a sample of 1,056 individuals from 235 families
selected from 13 clinical centers in the United States and Australia and
from a family ascertainment core center. They used family-based tests of
association. The sample consisted of 426 affected and 579 unaffected
family members; 51 individuals had unclear PD status. Both individual
SNPs and SNP haplotypes in the MAPT gene were analyzed. Significant
evidence of association was found for 3 of the 5 SNPs tested. Strong
evidence of association was found with haplotype analysis, with a
positive association with 1 haplotype (p = 0.009) and a negative
association with another haplotype (p = 0.007). Substantial linkage
disequilibrium (p less than 0.001) was detected between 4 of the 5 SNPs.
The study was interpreted as implicating MAPT as a susceptibility gene
for idiopathic Parkinson disease.

Kwok et al. (2005) identified 2 functional SNPs in the GSK3B (605004)
gene that influenced GSK3B transcriptional activity and correlated with
enhanced phosphorylation of MAPT in vitro, respectively. Conditional
logistic regression analysis of the genotypes of 302 Caucasian PD
patients and 184 Chinese PD patients found an association between the
GSK3B polymorphisms, MAPT haplotype, and risk of PD. Kwok et al. (2005)
concluded that GSK3B polymorphisms interact with MAPT haplotypes to
modify disease risk in PD.

Among 52 Finnish patients with PD, Mattila et al. (2002) found an
increased frequency of the interleukin 1-beta gene (IL1B; 147720) -511
polymorphism compared to controls (allele frequency of 0.96 in PD and
0.73 in controls; p = 0.001). The calculated relative risk of PD for
patients carrying at least one IL1B allele was 8.8.

West et al. (2002) reported that a single-nucleotide polymorphism within
the parkin core promoter, -258T/G, is located in a region of DNA that
binds nuclear protein from human substantia nigra in vitro, and
functionally affects gene transcription. In a population-based series of
296 PD cases and 184 controls, the -258G allele was associated with
idiopathic PD (odds ratio 1.52, P less than 0.05).

Excess of nitric oxide (NO) has been shown to exert neurotoxic effects
in the brain. Moreover, inhibition of 2 enzyme isoforms of nitric oxide
synthase (NOS; see 163731), neuronal NOS (nNOS) and inducible NOS
(iNOS), results in neuroprotective effects in the MPTP model of PD.
Levecque et al. (2003) performed a community-based case-control study of
209 PD patients enrolled in a French health insurance organization for
agricultural workers and 488 European controls. Associations were
observed with a G-to-A polymorphism in exon 22 of iNOS, designated iNOS
22 (OR for AA carriers, 0.50; 95% CI, 0.29-0.86; p = 0.01), and a T-to-C
polymorphism in exon 29 of nNOS, designated nNOS 29 (OR for carriers of
the T allele, 1.53; 95% CI, 1.08-2.16; p = 0.02). No association was
observed with a T-to-C polymorphism in exon 18 of nNOS, designated nNOS
18. Moreover, a significant interaction of the nNOS polymorphisms with
current and/or past cigarette smoking was found (nNOS 18, p = 0.05; nNOS
29, p = 0.04). Levecque et al. (2003) suggested that NOS1 may be a
modifier gene in PD.

Chan et al. (2003) found that the slow acetylator (243400) genotype for
N-acetyltransferase-2 (NAT2; 612182) was associated with PD in Hong Kong
Chinese. The frequency of slow acetylator genotype was significantly
higher in 99 patients with PD than in 126 control subjects (68.7% vs
28.6%) with an odds ratio of 5.53 after adjusting for age, sex, and
smoking history. In a subgroup analysis, smoking had no modifying effect
on the association between genotype and PD.

In 2 apparently sporadic patients with Parkinson disease, Marx et al.
(2003) found an arg621-to-cys (R621C) mutation in synphilin-1
(603779.0001).

Li et al. (2002) reported genetic linkage of a locus controlling age at
onset in Alzheimer disease (AD; 104300) and PD to a 15-cM region on
chromosome 10q. Li et al. (2003) combined gene expression studies on
hippocampus obtained from AD patients and controls with their previously
reported linkage data to identify 4 candidate genes. Allelic association
studies for age-at-onset effects in 1,773 AD patients and 1,041
relatives and 635 PD patients and 727 relatives further limited
association to GSTO1 (605482) (p = 0.007) and a second transcribed
member of the GST omega class, GSTO2 (612314) (p = 0.005), located next
to GSTO1. The authors suggested that GSTO1 may be involved in the
posttranslational modification of IL1B.

Theuns et al. (2006) pointed out that it is widely accepted that genetic
causes of susceptibility to complex diseases reflect a different
spectrum of sequence variants than mutations that dominate monogenic
disorders. This spectrum includes mutations that alter gene expression;
in particular, promoter mutations have been shown to result in inherited
diseases, including neurodegenerative brain diseases. They pointed to
the fact that in Parkinson disease, 2 variants in the 5-prime regulatory
region of NR4A2 (601828.0001 and 601828.0002) were found to be
associated with familial PD and markedly reduced NR4A2 mRNA levels.
Also, multiple association studies showed that variations in the 5-prime
regulatory regions of SNCA (163890) and PARK2 (602544) increase PD
susceptibility, with some variations increasing disease risk by
modulating gene transcription. In Alzheimer disease (104300), promoter
mutations in PSEN1 (104311) can explain the increased risk for
early-onset AD by decreasing expression levels of PSEN1 in neurons.

Considering 4 putative PD risk regions, SNCA, MAPT, GAK, and HLA-DRA in
2,000 late-onset PD patients and 1,986 unaffected controls from the NGRC
population, Hamza et al. (2010) found that the risk of Parkinson disease
was doubled for individuals who had 4 risk alleles (OR of 2.49, p = 6.5
x 10(-8)), and was increased 5-fold for individuals who had 6 or more
risk alleles (OR of 4.95, p = 5.5 x 10(-13)). These findings supported
the notion that Parkinson disease risk is due to cumulative effects of
risk factors that each have a modest individual effect.

- Association with the Glucocerebrosidase (GBA) Gene

An association has been reported between parkinsonism and type I Gaucher
disease (230800) (Neudorfer et al., 1996; Tayebi et al., 2001; Bembi et
al., 2003), the most prevalent, recessively inherited disorder of
glycolipid storage. Simultaneous occurrence of Parkinson disease and
Gaucher disease is marked by atypical parkinsonism generally presenting
by the fourth through sixth decades of life. The combination progresses
inexorably and is refractory to conventional anti-Parkinson therapy
(Varkonyi et al., 2003).

Aharon-Peretz et al. (2004) studied the association of Parkinson disease
with Gaucher disease, which is caused by mutation in the GBA gene
(606463), which encodes the lysosomal enzyme glucocerebrosidase. They
screened 99 Ashkenazi patients with idiopathic Parkinson disease, 74
Ashkenazi patients with Alzheimer disease, and 1,543 healthy Ashkenazi
Jews for the 6 GBA mutations that are most common among Ashkenazi Jews.
One or 2 mutant GBA alleles were found in 31 patients with Parkinson
disease (31.3%): 28 were heterozygous and 3 were homozygous for one of
these mutations. Among the 74 patients with Alzheimer disease, 3 (4.1%)
were carriers of Gaucher disease. Among the 1,543 controls, 95 (6.2%)
were carriers of Gaucher disease. Patients with Parkinson disease had
significantly greater odds of being carriers of Gaucher disease than did
patients with Alzheimer disease (OR = 10.8) or controls (OR = 7.0).
Among the patients with Parkinson disease, those who were carriers of
Gaucher disease were younger than those who were not carriers (mean age
at onset, 60.0 years vs 64.2 years, respectively). Aharon-Peretz et al.
(2004) suggested that some GBA mutations are susceptibility factors for
Parkinson disease.

Toft et al. (2006) did not find an association between PD and 2 common
GBA mutations (L444P; 606463.0001 and N370S; 606463.0003) among 311
Norwegian patients with Parkinson disease. Mutant GBA alleles were
identified in 7 (2.3%) patients and 8 (1.7%) controls.

Tan et al. (2007) identified a heterozygous GBA L444P mutation in 8
(2.4%) of 331 Chinese patients with typical Parkinson disease and none
of 347 controls. The age at onset was lower and the percentage of women
higher in patients with the L444P mutation compared to those without the
mutation. Tan et al. (2007) noted that the findings were significant
because Gaucher disease is extremely rare among the Chinese.

Gan-Or et al. (2008) found that 75 (17.9%) of 420 Ashkenazi Jewish
patients with PD carried a GBA mutation, compared to 4.2% of elderly and
6.35% of young controls. The proportion of severe GBA mutation carriers
among patients was 29% compared to 7% among young controls. Severe and
mild GBA mutations increased the risk of developing PD by 13.6- and
2.2-fold, and were associated with decreased age at PD onset. Gan-Or et
al. (2008) concluded that genetic variance in the GBA gene is a risk
factor for PD.

Gutti et al. (2008) identified the GBA L444P mutation in 4 (2.2%) of 184
Taiwanese patients with PD. Six other GBA variants were identified in 1
patient each, yielding a total of 7 different mutations in 10 patients
(5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA
gene would reveal additional variants that may contribute to PD.

Mata et al. (2008) identified heterozygosity for either the GBA L444P or
N370S mutation in 21 (2.9%) of 721 PD patients, 2 (3.5%) of 57 patients
with Lewy body dementia, and 2 (0.4%) of 554 control subjects
individuals, all of European origin. Mata et al. (2008) estimated that
the population-attributable risk for GBA mutations in Lewy body
disorders was only about 3% in patients of European ancestry.

In a 16-center worldwide study comprising 5,691 PD patients (including
780 Ashkenazi Jewish patients) and 4,898 controls (387 Ashkenazis),
Sidransky et al. (2009) demonstrated a strong association between GBA
mutations and Parkinson disease. Direct sequencing for only the L444P or
N370S mutations identified either mutation in 15% of Ashkenazi patients
and 3% of Ashkenazi controls. Among non-Ashkenazi individuals, either
mutation was found in 3% of patients and less than 1% of controls.
However, full gene sequencing identified GBA mutations in 7% of
non-Ashkenazi patients. The odds ratio for any GBA mutation in patients
compared to controls was 5.43 across all centers. Compared to PD
patients without GBA mutations, patients with GBA mutations presented
earlier with the disease, were more likely to have affected relatives,
and were more more likely to have atypical manifestations, including
cognitive defects. Sidransky et al. (2009) concluded that while GBA
mutations are not likely a mendelian cause of PD, they do represent a
susceptibility factor for development of the disorder.

Neumann et al. (2009) identified 14 different heterozygous mutations in
the GBA gene, in 33 (4.18%) of 790 British patients with Parkinson
disease and in 3 (1.17%) of 257 controls. Three novel mutations (see,
e.g., D443N; 606463.0048) were identified, and most common mutations
were L444P (in 11 patients), N370S (in 8 patients), and R463C (in 3
patients; 606463.0008). Four (12%) patients had a family history of the
disorder, whereas 29 (88%) had sporadic disease. The mean age at onset
was 52.7 years, and 12 (39%) patients had onset before age 50. Fifteen
(about 50%) patients with GBA mutations developed cognitive decline,
including visual hallucinations. The male to female ratio of GBA
carriers within the PD group was 5:2, which was significantly higher
than that of the whole study group. Most patients responded initially to
L-dopa treatment. Neuropathologic examination of 17 GBA mutation
carriers showed typical PD changes, with widespread and abundant
alpha-synuclein pathology, and most also had neocortical Lewy body
pathology. The prevalence of GBA mutations in British patients with
sporadic PD was 3.7%, indicating that mutations in the GBA gene may be
the most common risk factor for development of PD in this population. In
an accompanying letter, Gan-Or et al. (2009) found that the data
presented by Neumann et al. (2009) indicated that patients with mild GBA
mutations had a later age at onset (62.9 years vs 49.8 years) and lower
frequency of cognitive symptoms (25% vs 55.6%) compared to patients with
severe GBA mutations.

Alcalay et al. (2010) identified mutations in the GBA gene in 64 (6.7%)
of 953 patients with early-onset PD before age 51, including 77 and 139
individuals of Hispanic and Jewish ancestry, respectively. There were 18
heterozygous L444P carriers, 38 heterozygous N370S carriers, and 2
homozygous N370S carriers. Six of the 64 patients had a GBA mutation and
another mutation in the LRRK2 or PRKN (PARK2; 602544) genes.

- Modifier Genes

Plaitakis et al. (2010) identified a 1492T-G polymorphism in the GLUD2
gene (S445A; 300144.0001) that was associated with earlier age of onset
in 2 cohorts of patients with Parkinson disease. Among 584 Greek
patients, 1492G hemizygous males developed PD 8 to 13 years earlier than
did patients with the T (p = 0.003), the G/T (p less than 0.001), or the
T/T (p = 0.01) genotype. Among 224 North American patients, 1492G
hemizygotes also developed PD earlier than those with other genotypes,
but the mean age differences reached statistical significance only when
G hemizygotes were compared to G/T heterozygotes (mean age difference:
13.1 years, p less than 0.05). The substitution was demonstrated to
confer a gain of function, which Plaitakis et al. (2010) postulated may
increase glutamate oxidation and the production of reactive oxygen
species in the brain.

GENOTYPE/PHENOTYPE CORRELATIONS

Mutations in the LRRK2 gene (609007) and the GBA gene commonly
predispose to PD in individuals of Ashkenazi Jewish descent. Gan-Or et
al. (2010) screened a cohort of 600 Ashkenazi PD patients for the common
LRRK2 G2019S mutation (609007.0006) and for 8 GBA mutations. Among all
patients, 117 (19.5%) were heterozygous for GBA mutations, and 82
(13.7%) were heterozygous for the LRRK2 G2019S mutation, including 8
patients carrying both GBA and LRRK2 mutations. There were 6 (1.0%)
homozygotes or compound heterozygotes GBA mutations carriers, and 1
(0.2%) patient homozygote for G2019S. Carriers of LRRK2 G2019S or GBA
mutations had a significantly earlier average age at onset (57.5 and
57.7 years) than noncarriers (61.0 years); the 8 with mutations in both
genes had a similar average age at onset (57.4 years). A phenotypic
comparison of those with the G2019S mutation, GBA mutations, and
noncarriers of these mutations showed that more of those with the G2019S
mutation reported muscle stiffness/rigidity (p = 0.007) and balance
disturbances (p = 0.008), while more GBA mutation carriers reported
slowness/bradykinesia (p = 0.021). However, the most common presenting
symptom in both groups was tremor (about 50%). These results suggested
distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD
in some cases.

PATHOGENESIS

Nussbaum and Polymeropoulos (1997) stated that the motor symptoms in
Parkinson disease are generally thought to result from the deficiency or
dysfunction of dopamine or dopaminergic neurons in the substantia nigra,
regardless of etiology.

Auluck et al. (2002) found that Lewy bodies and Lewy neurites in
postmortem brain tissue from Parkinson disease patients immunostained
for the molecular chaperones HSP70 (see 140550) and HSP40 (see 604572),
suggesting that chaperones may play a role in Parkinson disease
progression, as was demonstrated in their studies in flies carrying
mutated alpha-synuclein (163890) in which coexpression of human HSP70
mitigated the loss of dopaminergic neurons.

Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin
(RELN; 600514) fragment in CSF from 19 patients with AD compared to 11
nondemented controls. Western blot and PCR analysis confirmed increased
levels of reelin protein and mRNA in tissue samples from the frontal
cortex of AD patients. Reelin was not increased in plasma samples,
suggesting distinct cellular origins. The reelin 180-kD fragment was
also increased in CSF samples of other neurodegenerative disorders,
including frontotemporal dementia, PSP, and PD.

Cooper et al. (2006) found that the earliest defect following
alpha-synuclein expression in yeast was a block in endoplasmic
reticulum-to-Golgi vesicular trafficking. In a genomewide screen, the
largest class of toxicity modifiers were proteins functioning at this
same step, including the Rab guanosine triphosphate Ypt1p, which
associated with cytoplasmic alpha-synuclein inclusions. Elevated
expression of Rab1 (179508), the mammalian Ypt1 homolog, protected
against alpha-synuclein-induced dopaminergic neuron loss in animal
models of PD. Thus, Cooper et al. (2006) concluded that
synucleinopathies may result from disruptions in basic cellular
functions that interface with the unique biology of particular neurons
to make them especially vulnerable.

Outeiro et al. (2007) identified a potent inhibitor of sirtuin-2
(604480) and found that inhibition of SIRT2 rescued alpha-synuclein
toxicity and modified inclusion morphology in a cellular model of
Parkinson disease. Genetic inhibition of SIRT2 via small interfering RNA
similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors
protected against dopaminergic cell death both in vitro and in a
Drosophila model of PD. Outeiro et al. (2007) concluded that their
results suggest a link between neurodegeneration and aging.

Muqit et al. (2006) provided a review of the role of mitochondrial
dysfunction, including oxidative damage and apoptosis, in the
pathogenesis of Parkinson disease.

Elstner et al. (2009) performed whole-genome expression profiling of
isolated substantia nigra neurons taken from 8 patients with PD and 9
controls. Four differentially expressed genes were identified in
candidate PD pathways: MTND2 (516001, p = 7.14 x 10(-7)); PDXK (179020,
p = 3.27 x 10(-6)); SRGAP3 (606525, p = 5.65 x 10(-6)); TRAPPC4 (610971,
p = 5.81 x 10(-6)). Population-based studies found an association
between dbSNP rs2010795 in the PDXK gene and increased risk of PD in
German (p = 0.00032), British (p = 0.028), and Italian (p = 0.0025)
cohorts (combined p = 1.2 x 10(-7); OR of 1.3) totaling 1,232 PD
patients and 2,802 controls. Elstner et al. (2009) suggested that
vitamin B6 status and metabolism may influence disease risk in PD.
However, neither Guella et al. (2010) nor Vilarino-Guell et al. (2010)
could replicate the association with dbSNP rs2010795 in their respective
studies of 920 Italian PD patients and 920 Italian controls and of 6
independent populations from Europe, North America, and Asia totaling
1,977 PD patients and 1,907 controls.

In brains from patients with Parkinson disease, Minones-Moyano et al.
(2011) found decreased expression of MIRN34B (611374) and MIRN34C
(611375) in areas with variable neuropathologic affectation at different
clinical stages of the disease, including the amygdala, frontal cortex,
substantia nigra, and cerebellum. Misregulation of MIRN34B/C was
detected in pre-motor stages of the disease as well, particularly in the
amygdala. Depletion of MIRN34B or MIRN34C in differentiated dopaminergic
neuronal cells resulted in a moderate reduction in cell viability that
was accompanied by altered mitochondrial function and dynamics,
oxidative stress, and reduction in total cellular ATP content.
Downregulation of these miRNAs was associated with a decrease in the
expression of DJ1 (602533) and PARK2 (602544), 2 genes associated with
PD, in cell studies and in patient brain tissue. The findings suggested
that early deregulation of MIRN34B and MIRN34C can trigger downstream
transcriptome alterations underlying mitochondrial dysfunction and
oxidative stress, which ultimately compromise cell viability in PD.

POPULATION GENETICS

Trenkwalder et al. (1995) used a door-to-door survey to investigate the
prevalence of parkinsonism in a rural Bavarian population of individuals
older than 65 years. In this population, the prevalence of Parkinson
disease was 0.71%; drug-induced parkinsonism, 0.41%; vascular
parkinsonism, 0.20%; multiple systems atrophy, 0.31%; Fahr disease,
0.10%; and normal pressure hydrocephalus, 0.41%. Fifty percent of these
cases were newly diagnosed.

In a community-based survey of Singaporeans (9,000 Chinese, 3,000
Malays, and 3,000 Indians) aged 50 years and older, Tan et al. (2004)
found that the prevalence rate of PD was approximately 0.30%, which is
comparable to that of Western countries.

In a study of over 14,000 twin pairs in the Swedish Twin Registry,
Wirdefeldt et al. (2004) found that only 2 twin pairs were concordant
for PD, suggesting that environmental factors were more important in the
development of the disease in this population.

HISTORY

Parkinson disease was first described by physician James Parkinson as a
'shaking palsy' in 1817. Stien (2005) proposed that William Shakespeare
(1564-1616) referred to the disease as a 'palsy' of old age in several
of his plays, indicating that the first European reference to the
disease occurred in the late 16th century.

Zhang et al. (2006) provided a detailed review of early Chinese
descriptions of Parkinson disease, including contemporary therapeutic
recommendations. The evidence from classic sources of traditional
Chinese medicine strongly suggested that PD was known to medical
scholars in China as early as 425 B.C.; the first clear description of a
clinical case occurred during the Jin dynasty in late 12th century A.D.

ANIMAL MODEL

Clarke et al. (2000) studied the kinetics of neuronal death in 12 models
of photoreceptor degeneration, hippocampal neurons undergoing
excitotoxic cell death, a mouse model of cerebellar degeneration, and in
Parkinson and Huntington (143100) diseases. In all models the kinetics
of neuronal death were exponential and better explained by mathematical
models in which the risk of cell death remains constant or decreases
exponentially with age. These kinetics argue against the cumulative
damage hypothesis; instead, the time of death in any neuron is random.
Clarke et al. (2000) argued that their findings are most simply
accommodated by a '1-hit' biochemical model in which mutation imposes a
mutant steady state on the neuron and a single event randomly initiates
cell death. This model appears to be common to many forms of
neurodegeneration and has implications for therapeutic strategies in
that the likelihood that a mutant neuron can be rescued by treatment is
not diminished by age, and therefore treatment at any stage of illness
is likely to confer benefit.

Progressive postnatal depletion of dopaminergic cells has been
demonstrated in weaver mice, a mouse model of Parkinson disease
associated with homozygosity for a mutation in the H54 region of Girk2,
a putative G protein inward rectifier protein potassium channel.
Bandmann et al. (1996) found no mutations of the pore region in KCNJ6
(600877), the human homolog, in 50 cases of Parkinson disease, 23 of
which were index cases of familial Parkinson disease.

Transgenic Drosophila expressing human alpha-synuclein carrying the
ala30-to-pro (A30P; 163890.0002) mutation faithfully replicate essential
features of human Parkinson disease, including age-dependent loss of
dopaminergic neurons, Lewy body-like inclusions, and locomotor
impairment. Scherzer et al. (2003) characterized expression of the
entire Drosophila genome at presymptomatic, early, and advanced disease
stages. Fifty-one signature transcripts were tightly associated with
A30P alpha-synuclein expression. At the presymptomatic stage, expression
changes revealed specific pathology. In age-matched transgenic
Drosophila expressing the arg406-to-trp mutation in tau (157140.0003),
the transcription of mutant alpha-synuclein-associated genes was normal,
suggesting highly distinct pathways of neurodegeneration.

Landau et al. (2005) found that Fas (TNFRSF6; 134637)-deficient
lymphoproliferative mice developed a PD phenotype, characterized by
extensive nigrostriatal degeneration accompanied by tremor, hypokinesia,
and loss of motor coordination, after treatment with MPTP at a dose that
caused no phenotype in wildtype mice. Mice with mutated Fasl (TNFSF6;
134638) and generalized lymphoproliferative disease had an intermediate
phenotype. Treatment of cultured midbrain neurons with Fasl to induce
Fas signaling protected them from MPTP toxicity. Mice lacking only Fas
exon 9, which encodes the death domain, but retaining the intracellular
Fas domain and cell surface expression of Fas, were resistant to MPTP.
Peripheral blood lymphocytes from patients with idiopathic PD showed a
highly significant deficit in their ability to upregulate Fas after
mitogen stimulation. Landau et al. (2005) concluded that reduced FAS
expression increases susceptibility to neurodegeneration and that FAS
has a role in neuroprotection.

- Therapeutic Strategies

Kordower et al. (2000) tested lentiviral vector delivery of glial cell
line-derived neurotrophic factor (GDNF; 600837), or lenti-GDNF, for its
trophic effects upon degenerating nigrostriatal neurons in nonhuman
primate models of Parkinson disease. The authors injected lenti-GDNF
into the striatum and substantia nigra of nonlesioned aged rhesus
monkeys or young adult rhesus monkeys treated 1 week prior with MPTP, a
neurotoxin known to specifically damage dopamine neurons. Extensive GDNF
expression with anterograde and retrograde transport was seen in all
animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In
MPTP-treated monkeys, lenti-GDNF reversed functional deficits and
completely prevented nigrostriatal degeneration. Additionally,
lenti-GDNF injections to intact rhesus monkeys revealed long-term gene
expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment
reversed motor deficits in a hand-reach task. Kordower et al. (2000)
concluded that GDNF delivery using a lentiviral vector system can
prevent nigrostriatal degeneration and induce regeneration in primate
models of PD and might be a viable therapeutic strategy for PD patients.

Luo et al. (2002) noted that a disinhibited and overactive subthalamic
nucleus (STN) alters basal ganglia network activity in PD, and that
electrical inhibition, pharmacologic silencing, and STN ablation can
improve the motor symptoms in PD, presumably by leading to suppression
of firing activity of neurons in the substantia nigra (SN). Using a
recombinant adeno-associated virus to transduce excitatory glutaminergic
neurons in the rat STN with glutamic acid decarboxylase (GAD), the
enzyme that catalyzes synthesis of the inhibitory neurotransmitter GABA,
Luo et al. (2002) showed that the neurons expressed the GAD gene and
changed from largely excitatory to predominantly inhibitory, resulting
in decreased excitatory and increased inhibitory response in the
substantia nigra. Moreover, the increased inhibitory tone provided
neuroprotection to the dopaminergic cells in response to toxic insult.
Rats with the transduced gene showed significant improvement from the
parkinsonian behavioral phenotype. Luo et al. (2002) emphasized the
plasticity in neurotransmission in the mammalian brain.

Teismann et al. (2003) showed that cyclooxygenase-2 (COX2; 600262), the
rate-limiting enzyme in prostaglandin E2 synthesis, is upregulated in
brain dopaminergic neurons of both PD and the MPTP mouse model of that
disorder. They demonstrated further that targeting COX2 does not protect
against MPTP-induced dopaminergic neurodegeneration by mitigating
inflammation. Instead, they provided evidence that COX2 inhibition
prevents the formation of the oxidant species of dopamine-quinone, which
has been implicated in the pathogenesis of PD. This study supported a
critical role for COX2 in both the pathogenesis and selectivity of the
PD neurodegenerative process. Because of the safety record of the COX2
inhibitors, and their ability to penetrate the blood-brain barrier,
these drugs may be therapies for PD.

The striatum is a major forebrain nucleus that integrates cortical and
thalamic afferents and forms the input nucleus of the basal ganglia.
Striatal projection neurons target the substantia nigra pars reticulata
(direct pathway) or the lateral globus pallidus (indirect pathway).
Kreitzer and Malenka (2007) showed that excitatory synapses onto
indirect-pathway medium spiny neurons exhibit higher release probability
and larger NMDA receptor currents than direct-pathway synapses.
Moreover, indirect-pathway medium spiny neurons selectively express
endocannabinoid-mediated long-term depression (eCB-LTD), which requires
dopamine D2 receptor (126450) activation. In models of Parkinson
disease, indirect-pathway eCB-LTD is absent but is rescued by a D2
receptor agonist or inhibitors of endocannabinoid degradation.
Administration of these drugs together in vivo in mice reduced
parkinsonian motor deficits, suggesting that endocannabinoid-mediated
depression of indirect-pathway synapses has a critical role in the
control of movement.

Kravitz et al. (2010) reported direct activation of basal ganglia
circuitry in vivo, using optogenetic control of direct- and
indirect-pathway medium spiny projection neurons, achieved through
Cre-dependent viral expression of channelrhodopsin-2 in the striatum of
BAC transgenic mice expressing Cre recombinase under control of
regulatory elements for the dopamine D1 (126449) or D2 receptors.
Bilateral excitation of indirect-pathway medium spiny projection neurons
elicited a parkinsonian state distinguished by increased freezing,
bradykinesia, and decreased locomotor initiations. In contrast,
activation of direct-pathway medium spiny projection neurons reduced
freezing and increased locomotion. In a mouse model of Parkinson
disease, activation of the direct pathway completely rescued deficits in
freezing, bradykinesia, and locomotor initiation. Kravitz et al. (2010)
concluded that their data establish a critical role for basal ganglia
circuitry in the bidirectional regulation of motor behavior and indicate
that modulation of direct-pathway circuitry may represent an effective
therapeutic strategy for ameliorating parkinsonian motor deficits.

Chan et al. (2007) found that dopamine-containing neurons in the
substantia nigra in mice relied on L-type voltage-gated calcium channels
(see, e.g., CACNA1S, 114208) to drive pacemaking. The reliance on these
calcium channels increased with age, and juvenile neurons tended to use
sodium-powered cation channels. The mechanism used by juvenile neurons
remained latent in adulthood, but pharmacologic (isradipine) or
gene-mediated blocking of the calcium channels in adult neurons induced
a reversion to the juvenile form of pacemaking. Such blocking of calcium
influx protected dopamine-containing neurons in both in vitro and in
vivo mouse models of Parkinson disease. The findings were consistent
with a theory of pathogenesis in which activity-dependent calcium influx
results in intracellular calcium accumulation that becomes toxic to
these neurons with age.

Sotnikova et al. (2006) developed a novel acute mouse model of severe
dopamine deficiency using Dat (SLC6A3; 126455)-null mice and
pharmacologic inhibition of tyrosine hydroxylase. Dopamine-deficient
Dat-null (DDD) mice demonstrated severe akinesia, rigidity, tremor, and
ptosis, similar to behaviors observed in patients with Parkinson
disease. Interestingly, DDD mice were able to swim in water, indicating
that certain movements and conditions can occur independently of
dopamine. Dopamine agonists such as L-dopa temporarily restored
locomotion in DDD mice, and amphetamine derivatives showed effectiveness
in reducing motor abnormalities in DDD mice. Sotnikova et al. (2006)
noted that the DDD mouse model provides a unique opportunity to screen
potential therapeutic agents for the treatment of Parkinson disease.

Berman et al. (2011) found that Slc1a1 (133550)-null mice developed
age-dependent progressive loss of dopaminergic neurons in the substantia
nigra, with more than 40% of these neurons lost by age 12 months, and
microglial activation in the substantia nigra. Mutant mice showed
impaired motor performance compared to wildtype mice. These features
were similar to those found in humans with Parkinson disease.
Dopaminergic neurons in the Slc1a1-null mice showed evidence of
increased oxidative stress. Long-term treatment of mutant mice with
N-acetylcysteine resulted in increased levels of glutathione, prevented
dopaminergic neuronal loss, and resulted in improved motor performance.
Berman et al. (2011) suggested that the Slc1a1-null mouse may be a
useful model for the chronic neuronal oxidative stress that occurs in
PD.

*FIELD* SA
Duvoisin (1986)
*FIELD* RF
1. Aharon-Peretz, J.; Rosenbaum, H.; Gershoni-Baruch, R.: Mutations
in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi
Jews. New Eng. J. Med. 351: 1972-1977, 2004.

2. Alcalay, R. N.; Caccappolo, E.; Mejia-Santana, H.; Tang, M. X.;
Rosado, L.; Ross, B. M.; Verbitsky, M.; Kisselev, S.; Louis, E. D.;
Comella, C.; Colcher, A.; Jennings, D.; and 21 others: Frequency
of known mutations in early-onset Parkinson disease: implication for
genetic counseling: the Consortium on Risk for Early Onset Parkinson
Disease study. Arch. Neurol. 67: 1116-1122, 2010.

3. Allan, W.: Inheritance of shaking palsy. Arch. Intern. Med. 60:
424-436, 1937.

4. Auluck, P. K.; Chan, H. Y. E.; Trojanowski, J. Q.; Lee, V. M.-Y.;
Bonini, N. M.: Chaperone suppression of alpha-synuclein toxicity
in a Drosophila model for Parkinson's disease. Science 295: 865-868,
2002.

5. Ballanger, B.; Strafella, A. P.; van Eimeren, T.; Zurowski, M.;
Rusjan, P. M.; Houle, S.; Fox, S. H.: Serotonin 2A receptors and
visual hallucinations in Parkinson disease. Arch. Neurol. 67: 416-421,
2010.

6. Bandmann, O.; Davis, M. B.; Marsden, C. D.; Wood, N. W.: The human
homologue of the weaver mouse gene in familial and sporadic Parkinson's
disease. Neuroscience 72: 877-879, 1996.

7. Barbeau, A.; Cloutier, T.; Roy, M.; Plasse, L.; Paris, S.; Poirier,
J.: Ecogenetics of Parkinson's disease: 4-hydroxylation of debrisoquine. Lancet 326:
1213-1216, 1985. Note: Originally Volume II.

8. Barbeau, A.; Pourcher, E.: New data on the genetics of Parkinson's
disease. Canad. J. Neurol. Sci. 9: 53-60, 1982.

9. Barbeau, A.; Pourcher, E.: Genetics of early onset Parkinson disease.In:
Yahr, M. D.: Current Concepts of Parkinson Disease and Related Disorders.
Amsterdam: Excerpta Medica (pub.) 1983. Pp. 1-16.

10. Bell, J.; Clark, A. J.: A pedigree of paralysis agitans. Ann.
Eugen. 1: 455-462, 1926.

11. Bembi, B.; Zambito Marsala, S.; Sidransky, E.; Ciana, G.; Carrozzi,
M.; Zorzon, M.; Martini, C.; Gioulis, M.; Pittis, M. G.; Capus, L.
: Gaucher's disease with Parkinson's disease: clinical and pathological
aspects. Neurology 61: 99-101, 2003.

12. Berman, A. E.; Chan, W. Y.; Brennan, A. M.; Reyes, R. C.; Adler,
B. L.; Suh, S. W.; Kauppinen, T. M.; Edling, Y.; Swanson, R. A.:
N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1-/-
mouse. Ann. Neurol. 69: 509-520, 2011.

13. Bonifati, V.; Fabrizio, E.; Vanacore, N.; De Mari, M.; Meco, G.
: Familial Parkinson's disease: a clinical genetic analysis. Canad.
J. Neurol. Sci. 22: 272-279, 1995. Note: Erratum: Canad. J. Neurol.
Sci. 23: 158 only, 1996.

14. Bordet, R.; Broly, F.; Destee, A.; Libersa, C.: Genetic polymorphism
of cytochrome P450 2D6 in idiopathic Parkinson disease and diffuse
Lewy body disease. Clin. Neuropharmacol. 17: 484-488, 1994.

15. Botella-Lopez, A.; Burgaya, F.; Gavin, R.; Garcia-Ayllon, M. S.;
Gomez-Tortosa, E.; Pena-Casanova, J.; Urena, J. M.; Del Rio, J. A.;
Blesa, R.; Soriano, E.; Saez-Valero, J.: Reelin expression and glycosylation
patterns are altered in Alzheimer's disease. Proc. Nat. Acad. Sci. 103:
5573-5578, 2006.

16. Calne, D. B.; Langston, J. W.: Aetiology of Parkinson's disease. Lancet 322:
1457-1459, 1983. Note: Originally Volume II.

17. Calne, S.; Schoenberg, B.; Martin, W.; Uitti, R. J.; Spencer,
P.; Calne, D. B.: Familial Parkinson's disease: possible role of
environmental factors. Canad. J. Neurol. Sci. 14: 303-305, 1987.

18. Chan, C. S.; Guzman, J. N.; Ilijic, E.; Mercer, J. N.; Rick, C.;
Tkatch, T.; Meredith, G. E.; Surmeier, D. J.: 'Rejuvenation' protects
neurons in mouse models of Parkinson's disease. Nature 447: 1081-1086,
2007.

19. Chan, D. K. Y.; Lam, M. K. P.; Wong, R.; Hung, W. T.; Wilcken,
D. E. L.: Strong association between N-acetyltransferase 2 genotype
and PD in Hong Kong Chinese. Neurology 60: 1002-1005, 2003.

20. Chung, C. Y.; Khurana, V.; Auluck, P. K.; Tardiff, D. F.; Mazzulli,
J. R.; Soldner, F.; Baru, V.; Lou, Y.; Freyzon, Y.; Cho, S.; Mungenast,
A. E.; Muffat, J.; and 10 others: Identification and rescue of
alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342:
983-987, 2013.

21. Clarke, G.; Collins, R. A.; Leavitt, B. R.; Andrews, D. F.; Hayden,
M. R.; Lumsden, C. J.; McInnes, R. R.: A one-hit model of cell death
in inherited neuronal degenerations. Nature 406: 195-199, 2000.

22. Constantinescu, R.; Romer, M.; Kieburtz, K.; DATATOP Investigators
of the Parkinson Study Group: Malignant melanoma in early Parkinson's
disease: the DATATOP trial. Mov. Disord. 22: 720-722, 2007.

23. Cooper, A. A.; Gitler, A. D.; Cashikar, A.; Haynes, C. M.; Hill,
K. J.; Bhullar, B.; Liu, K.; Xu, K.; Strathearn, K. E.; Liu, F.; Cao,
S.; Caldwell, K. A.; Caldwell, G. A.; Marsischky, G.; Kolodner, R.
D.; LaBaer, J.; Rochet, J.-C.; Bonini, N. M.; Lindquist, S.: Alpha-synuclein
blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's
models. Science 313: 324-328, 2006.

24. Corvol, J.-C.; Bonnet, C.; Charbonnier-Beaupel, F.; Bonnet, A.-M.;
Fievet, M.-H.; Bellanger, A.; Roze, E.; Meliksetyan, G.; Ben Djebara,
M.; Hartmann, A.; Lacomblez, L.; Vrignaud, C.; Zahr, N.; Agid, Y.;
Costentin, J.; Hulot, J.-S.; Vidailhet, M.: The COMT Val158Met polymorphism
affects the response to entacapone in Parkinson's disease: a randomized
crossover clinical trial. Ann. Neurol. 69: 111-118, 2011.

25. Di Monte, D. A.: Mitochondrial DNA and Parkinson's disease. Neurology 41
(5 Suppl. 2) -38-42, 1991.

26. Duvoisin, R. C.: Genetics of Parkinson's disease. Adv. Neurol. 45:
307-312, 1986.

27. Duvoisin, R. C.; Eldridge, R.; Williams, A.; Nutt, J.; Calne,
D.: Twin study of Parkinson disease. Neurology 31: 77-80, 1981.

28. Elstner, M.; Morris, C. M.; Heim, K.; Lichtner, P.; Bender, A.;
Mehta, D.; Schulte, C.; Sharma, M.; Hudson, G.; Goldwurm, S.; Giovanetti,
A.; Zeviani, M.; and 19 others: Single-cell expression profiling
of dopaminergic neurons combined with association analysis identifies
pyridoxal kinase as Parkinson's disease gene. Ann. Neurol. 66: 792-798,
2009.

29. Feany, M. B.: New genetic insights into Parkinson's disease. New
Eng. J. Med. 351: 1937-1940, 2004.

30. Ferreira, J.; Silva, J. M.; Freire, R.; Pignatelli, J.; Guedes,
L. C.; Feijo, A.; Rosa, M. M.; Coelho, M.; Costa, J.; Noronha, A.;
Hewett, R.; Gomes, A. M.; Cirne de Castro, J. L.; Rascol, O.; Sampaio,
C.: Skin cancers and precancerous lesions in Parkinson's disease
patients. Mov. Disord. 22: 1471-1475, 2007.

31. Fujita, M.; Ichise, M.; Zoghbi, S. S.; Liow, J.-S.; Ghose, S.;
Vines, D. C.; Sangare, J.; Lu, J.-Q.; Cropley, V. L.; Iida, H.; Kim,
K. M.; Cohen, R. M.; Bara-Jimenez, W.; Ravina, B.; Innis, R. B.:
Widespread decrease of nicotinic acetylcholine receptors in Parkinson's
disease. Ann. Neurol. 59: 174-177, 2006.

32. Gan-Or, Z.; Bar-Shira, A.; Mirelman, A.; Gurevich, T.; Kedmi,
M.; Giladi, N.; Orr-Urtreger, A.: LRRK2 and GBA mutations differentially
affect the initial presentation of Parkinson disease. Neurogenetics 11:
121-125, 2010.

33. Gan-Or, Z.; Giladi, N.; Orr-Urteger, A.: Differential phenotype
in Parkinson's disease patients with severe versus mild GBA mutations.
(Letter) Brain 132: e125, 2009. Note: Electronic Article.

34. Gan-Or, Z.; Giladi, N.; Rozovski, U.; Shifrin, C.; Rosner, S.;
Gurevich, T.; Bar-Shira, A.; Orr-Urtreger, A.: Genotype-phenotype
correlations between GBA mutations and Parkinson disease risk and
onset. Neurology 70: 2277-2283, 2008.

35. Gao, X.; Martin, E. R.; Liu, Y.; Mayhew, G.; Vance, J. M.; Scott,
W. K.: Genome-wide linkage screen in familial Parkinson disease identifies
loci on chromosomes 3 and 18. Am. J. Hum. Genet. 84: 499-504, 2009.

36. Gao, X.; Simon, K. C.; Han, J.; Schwarzschild, M. A.; Ascherio,
A.: Family history of melanoma and Parkinson disease risk. Neurology 73:
1286-1291, 2009.

37. Gao, X.; Simon, K. C.; Han, J.; Schwarzschild, M. A.; Ascherio,
A.: Genetic determinants of hair color and Parkinson's disease risk. Ann.
Neurol. 65: 76-82, 2009.

38. Gasser, T.; Muller-Myhsok, B.; Wszolek, Z. K.; Durr, A.; Vaughan,
J. R.; Bonifati, V.; Meco, G.; Bereznai, B.; Oehlmann, R.; Agid, Y.;
Brice, A.; Wood, N.: Genetic complexity and Parkinson's disease.
(Letter) Science 277: 388-389, 1997.

39. Gill, S. S.; Patel, N. K.; Hotton, G. R.; O'Sullivan, K.; McCarter,
R.; Bunnage, M.; Brooks, D. J.; Svendsen, C. N.; Heywood, P.: Direct
brain infusion of glial cell line-derived neurotrophic factor in Parkinson
disease. Nature Med. 9: 589-595, 2003. Note: Addendum: Nature Med.
12: 479 only, 2006.

40. Gowers, W. R.: A Manual of Diseases of the Nervous System. Vol.
I. Diseases of the nerves and spinal cord. Philadelphia: P. Blakiston's
Son & Co. (pub.) (3rd ed.): 1900.

41. Guella, I.; Asselta, R.; Tesei, S.; Zini, M.; Pezzoli, G.; Duga,
S.: The PDXK rs2010795 variant is not associated with Parkinson disease
in Italy. Ann. Neurol. 67: 411-412, 2010.

42. Gutti, U.; Fung, H.-C.; Hruska, K. S.; LaMarca, M. E.; Chen, C.-M.;
Wu, Y.-R.; Sidransky, E.: The need for appropriate genotyping strategies
for glucocerebrosidase mutations in cohorts with Parkinson disease.
(Letter) Arch. Neurol. 65: 850-851, 2008.

43. Hamza, T. H.; Zabetian, C. P.; Tenesa, A.; Laederach, A.; Montimurro,
J.; Yearout, D.; Kay, D. M.; Doheny, K. F.; Paschall, J.; Pugh, E.;
Kusel, V. I.; Collura, R.; Roberts, J.; Griffith, A.; Samii, A.; Scott,
W. K.; Nutt, J.; Factor, S. A.; Payami, H.: Common genetic variation
in the HLA region is associated with late-onset sporadic Parkinson's
disease. Nature Genet. 42: 781-785, 2010.

44. Hernandez, E. H.: Pigmentation as a clue to understanding Parkinson's
disease and melanoma. (Letter) Ann. Neurol. 65: 759 only, 2009.

45. Ho, S. L.; Kapadi, A. L.; Ramsden, D. B.; Williams, A. C.: An
allelic association study of monoamine oxidase B in Parkinson's disease. Ann.
Neurol. 37: 403-405, 1995.

46. Hughes, A. J.; Daniel, S. E.; Kilford, L.; Lees, A. J.: Accuracy
of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological
study of 100 cases. J. Neurol. Neurosurg. Psychiat. 55: 181-184,
1992.

47. Kessler, I. I.: Parkinson's disease in epidemiologic perspective. Adv.
Neurol. 19: 355-381, 1978.

48. Kissel, P.; Andre, J. M.: Maladie de parkinson et anosmie chez
deux jumelles monozygotiques. J. Genet. Hum. 24: 113-117, 1976.

49. Kondo, K.; Kurland, L. T.; Schull, W. J.: Parkinson's disease:
genetic analysis and evidence of a multifactorial etiology. Mayo
Clin. Proc. 48: 465-475, 1973.

50. Kordower, J. H.; Emborg, M. E.; Bloch, J.; Ma, S. Y.; Chu, Y.;
Leventhal, L.; McBride, J.; Chen, E.-Y.; Palfi, S.; Roitberg, B. Z.;
Brown, W. D.; Holden, J. E.; Pyzalski, R.; Taylor, M. D.; Carvey,
P.; Ling, Z.; Trono, D.; Hantraye, P.; Deglon, N.; Aebischer, P.:
Neurodegeneration prevented by lentiviral vector delivery of GDNF
in primate models of Parkinson's disease. Science 290: 767-773,
2000.

51. Kravitz, A. V.; Freeze, B. S.; Parker, P. R. L.; Kay, K.; Thwin,
M. T.; Deisseroth, K.; Kreitzer, A. C.: Regulation of parkinsonian
motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466:
622-626, 2010.

52. Kreitzer, A. C.; Malenka, R. C.: Endocannabinoid-mediated rescue
of striatal LTD and motor deficits in Parkinson's disease models. Nature 445:
643-647, 2007.

53. Kurth, J. H.; Kurth, M. C.; Poduslo, S. E.; Schwankhaus, J. D.
: Association of a monoamine oxidase B allele with Parkinson's disease. Ann.
Neurol. 33: 368-372, 1993.

54. Kwok, J. B. J.; Hallupp, M.; Loy, C. T.; Chan, D. K. Y.; Woo,
J.; Mellick, G. D.; Buchanan, D. D.; Silburn, P. A.; Halliday, G.
M.; Schofield, P. R.: GSK3B polymorphisms alter transcription and
splicing in Parkinson's disease. Ann. Neurol. 58: 829-839, 2005.

55. Landau, A. M.; Luk, K. C.; Jones, M.-L.; Siegrist-Johnstone, R.;
Young, Y. K.; Kouassi, E.; Rymar, V. V.; Dagher, A.; Sadikot, A. F.;
Desbarats, J.: Defective Fas expression exacerbates neurotoxicity
in a model of Parkinson's disease. J. Exp. Med. 202: 575-581, 2005.

56. Langston, J. W.; Ballard, P.; Tetrud, J. W.; Irwin, I.: Chronic
parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:
979-980, 1983.

57. Lazzarini, A. M.; Myers, R. H.; Zimmerman, T. R., Jr.; Mark, M.
H.; Golbe, L. I.; Sage, J. I.; Johnson, W. G.; Duvoisin, R. C.: A
clinical genetic study of Parkinson's disease: evidence for dominant
transmission. Neurology 44: 499-506, 1994.

58. Lees, A. J.; Hardy, J.; Revesz, T.: Parkinson's disease. Lancet 373:
2055-2066, 2009. Note: Erratum: Lancet 374: 684 only, 2009.

59. Levecque, C.; Elbaz, A.; Clavel, J.; Richard, F.; Vidal, J.-S.;
Amouyel, P.; Tzourio, C.; Alperovitch, A.; Chartier-Harlin, M.-C.
: Association between Parkinson's disease and polymorphisms in the
nNOS and iNOS genes in a community-based case-control study. Hum.
Molec. Genet. 12: 79-86, 2003.

60. Li, Y.-J.; Oliveira, S. A.; Xu, P.; Martin, E. R.; Stenger, J.
E.; Hulette, C.; Scherzer, C. R.; Hauser, M. A.; Scott, W. K.; Small,
G. W.; Nance, M. A.; Watts, R. L.; and 18 others: Glutathione S-transferase
omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum.
Molec. Genet. 12: 3259-3267, 2003. Note: Erratum: Hum. Molec. Genet.
13: 573 only, 2004.

61. Li, Y.-J.; Scott, W. K.; Hedges, D. J.; Zhang, F.; Gaskell, P.
C.; Nance, M. A.; Watts, R. L.; Hubble, J. P.; Koller, W. C.; Pahwa,
R.; Stern, M. B.; Hiner, B. C.; and 20 others: Age at onset in
two common neurodegenerative diseases is genetically controlled. Am.
J. Hum. Genet. 70: 985-993, 2002.

62. Luo, J.; Kaplitt, M. G.; Fitzsimons, H. L.; Zuzga, D. S.; Liu,
Y.; Oshinsky, M. L.; During, M. J.: Subthalamic GAD gene therapy
in a Parkinson's disease rat model. Science 298: 425-429, 2002.

63. Maher, N. E.; Currie, L. J.; Lazzarini, A. M.; Wilk, J. B.; Taylor,
C. A.; Saint-Hilaire, M. H.; Feldman, R. G.; Golbe, L. I.; Wooten,
G. F.; Myers, R. H.: Segregation analysis of Parkinson disease revealing
evidence for a major causative gene. Am. J. Med. Genet. 109: 191-197,
2002.

64. Maraganore, D. M.; de Andrade, M.; Lesnick, T. G.; Strain, K.
J.; Farrer, M. J.; Rocca, W. A.; Pant, P. V. K.; Frazer, K. A.; Cox,
D. R.; Ballinger, D. G.: High-resolution whole-genome association
study of Parkinson disease. Am. J. Hum. Genet. 77: 685-693, 2005.

65. Marder, K.; Levy, G.; Louis, E. D.; Mejia-Santana, H.; Cote, L.;
Andrews, H.; Harris, J.; Waters, C.; Ford, B.; Frucht, S.; Fahn, S.;
Ottman, R.: Familial aggregation of early- and late-onset Parkinson's
disease. Ann. Neurol. 54: 507-513, 2003. Note: Erratum: Ann. Neurol.
54: 693 only, 2003.

66. Markopoulou, K.; Wszolek, Z. K.; Pfeiffer, R. F.: A Greek-American
kindred with autosomal dominant, levodopa-responsive Parkinsonism
and anticipation. Ann. Neurol. 38: 373-378, 1995.

67. Martin, E. R.; Scott, W. K.; Nance, M. A.; Watts, R. L.; Hubble,
J. P.; Koller, W. C.; Lyons, K.; Pahwa, R.; Stern, M. B.; Colcher,
A.; Hiner, B. C.; Jankovic, J.; and 20 others: Association of single-nucleotide
polymorphisms of the Tau gene with late-onset Parkinson disease. JAMA 286:
2245-2250, 2001.

68. Marx, F. P.; Holzmann, C.; Strauss, K. M.; Li, L.; Eberhardt,
O.; Gerhardt, E.; Cookson, M. R.; Hernandez, D.; Farrer, M. J.; Kachergus,
J.; Engelender, S.; Ross, C. A.; Berger, K.; Schols, L.; Schulz, J.
B.; Riess, O.; Kruger, R.: Identification and functional characterization
of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease. Hum.
Molec. Genet. 12: 1223-1231, 2003.

69. Mata, I. F.; Samii, A.; Schneer, S. H.; Roberts, J. W.; Griffith,
A.; Leis, B. C.; Schellenberg, G. D.; Sidransky, E.; Bird, T. D.;
Leverenz, J. B.; Tsuang, D.; Zabetian, C. P.: Glucocerebrosidase
gene mutations: a risk factor for Lewy body disorders. Arch. Neurol. 65:
379-382, 2008.

70. Mata, I. F.; Yearout, D.; Alvarez, V.; Coto, E.; de Mena, L.;
Ribacoba, R.; Lorenzo-Betancor, O.; Samaranch, L.; Pastor, P.; Cervantes,
S.; Infante, J.; Garcia-Gorostiaga, I.; Sierra, M.; Combarros, O.;
Snapinn, K. W.; Edwards, K. L.; Zabetian, C. P.: Replication of MAPT
and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's
disease. Mov. Disord. 26: 819-823, 2011.

71. Mattila, K. M.; Rinne, J. O.; Lehtimaki, T.; Roytta, M.; Ahonen,
J.-P.; Hurme, M.: Association of an interleukin 1B gene polymorphism
(-511) with Parkinson's disease in Finnish patients. J. Med. Genet. 39:
400-402, 2002.

72. Minones-Moyano, E.; Porta, S.; Escaramis, G.; Rabionet, R.; Iraola,
S.; Kagerbauer, B.; Espinosa-Parrilla, Y.; Ferrer, I.; Estivill, X.;
Marti, E.: MicroRNA profiling of Parkinson's disease brains identifies
early downregulation of miR-34b/c which modulate mitochondrial function. Hum.
Molec. Genet. 20: 3067-3078, 2011.

73. Montgomery, E. B., Jr.; Baker, K. B.; Lyons, K.; Koller, W. C.
: Abnormal performance on the PD test battery by asymptomatic first-degree
relatives. Neurology 52: 757-762, 1999.

74. Muqit, M. M. K.; Gandhi, S.; Wood, N. W.: Mitochondria in Parkinson
disease: back in fashion with a little help from genetics. Arch.
Neurol. 63: 649-654, 2006.

75. Nathans, J.: Written in our genes? (Letter) Science 308: 1742
only, 2005.

76. Neudorfer, O.; Giladi, N.; Elstein, D.; Abrahamov, A.; Turezkite,
T.; Aghai, E.; Reches, A.; Bembi, B.; Zimran, A.: Occurrence of Parkinson's
syndrome in type I Gaucher disease. Quart. J. Med. 89: 691-694,
1996.

77. Neumann, J.; Bras, J.; Deas, E.; O'Sullivan, S. S.; Parkkinen,
L.; Lachmann, R. H.; Li, A.; Holton, J.; Guerreiro, R.; Paudel, R.;
Segarane, B.; Singleton, A.; Lees, A.; Hardy, J.; Houlden, H.; Revesz,
T.; Wood, N. W.: Glucocerebrosidase mutations in clinical and pathologically
proven Parkinson's disease. Brain 132: 1783-1794, 2009.

78. Nussbaum, R. L.; Ellis, C. E.: Alzheimer's disease and Parkinson's
disease. New Eng. J. Med. 348: 1356-1364, 2003. Note: Erratum: New
Eng. J. Med. 348: 2588 only, 2003.

79. Nussbaum, R. L.; Polymeropoulos, M. H.: Genetics of Parkinson's
disease. Hum. Molec. Genet. 6: 1687-1691, 1997.

80. Outeiro, T. F.; Kontopoulous, E.; Altmann, S. M.; Kufareva, I.;
Strathearn, K. E.; Amore, A. M.; Volk, C. B.; Maxwell, M. M.; Rochet,
J.-C.; McLean, P. J.; Young, A. B.; Abagyan, R.; Feany, M. B.; Hyman,
B. T.; Kazantsev, A. G.: Sirtuin 2 inhibitors rescue alpha-synuclein-mediated
toxicity in models of Parkinson's disease. Science 317: 516-519,
2007.

81. Paleacu, D.; Schechtman, E.; Inzelberg, R.: Association between
family history of dementia and hallucinations in Parkinson disease. Neurology 64:
1712-1715, 2005.

82. Pankratz, N.; Nichols, W. C.; Uniacke, S. K.; Halter, C.; Murrell,
J.; Rudolph, A.; Shults, C. W.; Conneally, P. M.; Foroud, T.; Parkinson
Study Group: Genome-wide linkage analysis and evidence of gene-by-gene
interactions in a sample of 362 multiplex Parkinson disease families. Hum.
Molec. Genet. 12: 2599-2608, 2003.

83. Pankratz, N.; Nichols, W. C.; Uniacke, S. K.; Halter, C.; Rudolph,
A.; Shults, C.; Conneally, P. M.; Foroud, T.; the Parkinson Study
Group: Genome screen to identify susceptibility genes for Parkinson
disease in a sample without parkin mutations. Am. J. Hum. Genet. 71:
124-135, 2002.

84. Pankratz, N.; Wilk, J. B.; Latourelle, J. C.; DeStefano, A. L.;
Halter, C.; Pugh, E. W.; Doheny, K. F.; Gusella, J. F.; Nichols, W.
C.; Foroud, T.; Myers, R. H.; The PSG-PROGENI and GenePD Investigators,
Coordinators and Molecular Genetic Laboratories: Genomewide association
study for susceptibility genes contributing to familial Parkinson
disease. Hum. Genet. 124: 593-605, 2009.

85. Parboosingh, J. S.; Rousseau, M.; Rogan, F.; Amit, Z.; Chertkow,
H.; Johnson, W. G.; Manganaro, F.; Schipper, H. N.; Curran, T. J.;
Stoessl, J.; Rouleau, G. A.: Absence of mutations in superoxide dismutase
and catalase genes in patients with Parkinson's disease. Arch. Neurol. 52:
1160-1163, 1995.

86. Parker, W. D.; Swerdlow, R. H.; Parks, J. K.; Davis, J. N., II;
Trimmer, P.; Bennett, J. P.; Wooten, G. F.: Parkinson disease in
twins. (Letter) JAMA 282: 1328 only, 1999.

87. Payami, H.; Bernard, S.; Larsen, K.; Kaye, J.; Nutt, J.: Genetic
anticipation in Parkinson's disease. Neurology 45: 135-138, 1995.

88. Plaitakis, A.; Latsoudis, H.; Kanavouras, K.; Ritz, B.; Bronstein,
J. M.; Skoula, I.; Mastorodemos, V.; Papapetropoulos, S.; Borompokas,
N.; Zaganas, I.; Xiromerisiou, G.; Hadjigeorgiou, G. M.; Spanaki,
C.: Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies
Parkinson's disease onset. Europ. J. Hum. Genet. 18: 336-341, 2010.

89. Plante-Bordeneuve, V.; Taussig, D.; Thomas, F.; Ziegler, M.; Said,
G.: A clinical and genetic study of familial cases of Parkinson's
disease. J. Neurol. Sci. 133: 164-172, 1995.

90. Polymeropoulos, M. H.: Reply to Scott et al. and Gasser et al.
(Letter) Science 277: 389 only, 1997.

91. Polymeropoulos, M. H.; Higgins, J. J.; Golbe, L. I.; Johnson,
W. G.; Ide, S. E.; Di Iorio, G.; Sanges, G.; Stenroos, E. S.; Pho,
L. T.; Schaffer, A. A.; Lazzarini, A. M.; Nussbaum, R. L.; Duvoisin,
R. C.: Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 274:
1197-1198, 1996.

92. Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.; Dehejia,
A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; Stenroos,
E. S.; Chandrasekharappa, S.; Athanassiadou, A.; Papepetropoulos,
T.; Johnson, W. G.; Lazzarini, A. M.; Duvoisin, R. C.; Di Iorio, G.;
Golbe, L. I.; Nussbaum, R. L.: Mutation in the alpha-synuclein gene
identified in families with Parkinson's disease. Science 276: 2045-2047,
1997.

93. Racette, B. A.; Rundle, M.; Wang, J. C.; Goate, A.; Saccone, N.
L.; Farrer, M.; Lincoln, S.; Hussey, J.; Smemo, S.; Lin, J.; Suarez,
B.; Parsian, A.; Perlmutter, J. S.: A multi-incident, Old-Order Amish
family with PD. Neurology 58: 568-574, 2002.

94. Sandy, M. S.; Armstrong, M.; Tanner, C. M.; Daly, A. K.; Di Monte,
D. A.; Langston, J. W.; Idle, J. R.: CYP2D6 allelic frequencies in
young-onset Parkinson's disease. Neurology 47: 225-230, 1996.

95. Satake, W.; Nakabayashi, Y.; Mizuta, I.; Hirota, Y.; Ito, C.;
Kubo, M.; Kawaguchi, T.; Tsunoda, T.; Watanabe, M.; Takeda, A.; Tomiyama,
H.; Nakashima, K.; and 10 others: Genome-wide association study
identifies common variants at four loci as genetic risk factors for
Parkinson's disease. (Letter) Nature Genet. 41: 1303-1307, 2009.

96. Schapira, A. H. V.: Nuclear and mitochondrial genetics in Parkinson's
disease. J. Med. Genet. 32: 411-414, 1995.

97. Scherzer, C. R.; Jensen, R. V.; Gullans, S. R.; Feany, M. B.:
Gene expression changes presage neurodegeneration in a Drosophila
model of Parkinson's disease. Hum. Molec. Genet. 12: 2457-2466,
2003.

98. Scott, W. K.; Nance, M. A.; Watts, R. L.; Hubble, J. P.; Koller,
W. C.; Lyons, K.; Pahwa, R.; Stern, M. B.; Colcher, A.; Hiner, B.
C.; Jankovic, J.; and 20 others: Complete genomic screen in Parkinson
disease: evidence for multiple genes. JAMA 286: 2239-2244, 2001.

99. Scott, W. K.; Stajich, J. M.; Yamaoka, L. H.; Speer, M. C.; Vance,
J. M.; Roses, A. D.; Pericak-Vance, M. A.; Deane Laboratory Parkinson
Disease Research Group: Genetic complexity and Parkinson's disease.
(Letter) Science 277: 387-388, 1997.

100. Sidransky, E.; Nalls, M. A.; Aasly, J. O.; Aharon-Peretz, J.;
Annesi, G.; Barbosa, E. R.; Bar-Shira, A.; Berg, D.; Bras, J.; Brice,
A.; Chen, C.-M.; Clark, L. N.; and 50 others: Multicenter analysis
of glucocerebrosidase mutations in Parkinson's disease. New Eng.
J. Med. 361: 1651-1661, 2009.

101. Simon, D. K.: Reply to Parker et al. (Letter) JAMA 282: 1328
only, 1999.

102. Simon-Sanchez, J.; Schulte, C.; Bras, J. M.; Sharma, M.; Gibbs,
J. R.; Berg, D.; Paisan-Ruiz, C.; Lichtner, P.; Scholz, S. W.; Hernandez,
D. G.; Kruger, R.; Federoff, M.; and 35 others: Genome-wide association
study reveals genetic risk underlying Parkinson's disease. (Letter) Nature
Genet. 41: 1308-1312, 2009.

103. Sommer, S. S.; Rocca, W. A.: Prion analogues and twin studies
in Parkinson's disease. Neurology 46: 273-275, 1996.

104. Sotnikova, T. D.; Caron, M. G.; Gainetdinov, R. R.: DDD mice,
a novel acute mouse model of Parkinson's disease. Neurology 67 (suppl.
2): S12-S17, 2006.

105. Spellman, G. G.: Report of familial cases of parkinsonism: evidence
of a dominant trait in a patient's family. JAMA 179: 372-374, 1962.

106. Stien, R.: Shakespeare on Parkinsonism. (Letter) Mov. Disord. 20:
768-769, 2005.

107. Sveinbjornsdottir, S.; Hicks, A. A.; Jonsson, T.; Petursson,
H.; Guomundsson, G.; Frigge, M. L.; Kong, A.; Gulcher, J. R.; Stefansson,
K.: Familial aggregation of Parkinson's disease in Iceland. New
Eng. J. Med. 343: 1765-1770, 2000.

108. Tan, E.-K.; Chua, E.; Fook-Chong, S. M.; Teo, Y.-Y.; Yuen, Y.;
Tan, L.; Zhao, Y.: Association between caffeine intake and risk of
Parkinson's disease among fast and slow metabolizers. Pharmacogenet.
Genomics 17: 1001-1005, 2007.

109. Tan, E.-K.; Kwok, H.-H.; Tan, L. C.; Zhao, W.-T.; Prakash, K.
M.; Au, W.-L.; Pavanni, R.; Ng, Y.-Y.; Satake, W.; Zhao, Y.; Toda,
T.; Liu, J.-J.: Analysis of GWAS-linked loci in Parkinson disease
reaffirms PARK16 as a susceptibility locus. Neurology 75: 508-512,
2010. Note: Erratum: Neurology 75: 1399 only, 2010.

110. Tan, E.-K.; Tong, J.; Fook-Chong, S.; Yih, Y.; Wong, M.-C.; Pavanni,
R.; Zhao, Y.: Glucocerebrosidase mutations and risk of Parkinson
disease in Chinese patients. Arch. Neurol. 64: 1056-1058, 2007.

111. Tan, L. C. S.; Venketasubramanian, N.; Hong, C. Y.; Sahadevan,
S.; Chin, J. J.; Krishnamoorthy, E. S.; Tan, A. K. Y.; Saw, S. M.
: Prevalence of Parkinson disease in Singapore: Chinese vs Malays
vs Indians. Neurology 62: 1999-2004, 2004.

112. Tanner, C. M.; Ottman, R.; Goldman, S. M.; Ellenberg, J.; Chan,
P.; Mayeux, R.; Langston, J. W.: Parkinson disease in twins: an etiologic
study. JAMA 281: 341-346, 1999.

113. Tardiff, D. F.; Jui, N. T.; Khurana, V.; Tambe, M. A.; Thompson,
M. L.; Chung, C. Y.; Kamadurai, H. B.; Kim, H. T.; Lancaster, A. K.;
Caldwell, K. A.; Caldwell, G. A.; Rochet, J.-C.; Buchwald, S. L.;
Lindquist, S.: Yeast reveal a 'druggable' Rsp5/Nedd4 network that
ameliorates alpha-synuclein toxicity in neurons. Science 342: 979-983,
2013.

114. Tayebi, N.; Callahan, M.; Madike, V.; Stubblefield, B. K.; Orvisky,
E.; Krasnewich, D.; Fillano, J. J.; Sidransky, E.: Gaucher disease
and parkinsonism: a phenotypic and genotypic characterization. Molec.
Genet. Metab. 73: 313-321, 2001.

115. Teismann, P.; Tieu, K.; Choi, D.-K.; Wu, D.-C.; Naini, A.; Hunot,
S.; Vila, M.; Jackson-Lewis, V.; Przedborski, S.: Cyclooxygenase-2
is instrumental in Parkinson's disease neurodegeneration. Proc. Nat.
Acad. Sci. 100: 5473-5478, 2003.

116. Teravainen, H.; Forgach, L.; Hietanen, M.; Schulzer, M.; Schoenberg,
B.; Calne, D. B.: The age of onset of Parkinson's disease: etiological
implications. Canad. J. Neurol. Sci. 13: 317-319, 1986.

117. Theuns, J.; Brouwers, N.; Engelborghs, S.; Sleegers, K.; Bogaerts,
V.; Corsmit, E.; De Pooter, T.; van Duijn, C. M.; De Deyn, P. P.;
Van Broeckhoven, C.: Promoter mutations that increase amyloid precursor-protein
expression are associated with Alzheimer disease. Am. J. Hum. Genet. 78:
936-946, 2006.

118. Toft, M.; Pielsticker, L.; Ross, O. A.; Aasley, J. O.; Farrer,
M. J.: Glucocerebrosidase gene mutations and Parkinson disease in
the Norwegian population. Neurology 66: 415-417, 2006.

119. Trenkwalder, C.; Schwarz, J.; Gebhard, J.; Ruland, D.; Trenkwalder,
P.; Hense, H.-W.; Oertel, W. H.: Starnberg trial on epidemiology
of parkinsonism and hypertension in the elderly: prevalence of Parkinson's
disease and related disorders assessed by a door-to-door survey of
inhabitants older than 65 years. Arch. Neurol. 52: 1017-1022, 1995.

120. Tune, L. E.; Folstein, M.; Rabins, P.; Jayaram, G.; McHugh, P.
: Familial manic-depressive illness and familial Parkinson's disease:
a case report. Johns Hopkins Med. J. 151: 65-70, 1982.

121. van der Walt, J. M.; Nicodemus, K. K.; Martin, E. R.; Scott,
W. K.; Nance, M. A.; Watts, R. L.; Hubble, J. P.; Haines, J. L.; Koller,
W. C.; Lyons, K.; Pahwa, R.; Stern, M. B.; and 15 others: Mitochondrial
polymorphisms significantly reduce the risk of Parkinson disease. Am.
J. Hum. Genet. 72: 804-811, 2003.

122. Varkonyi, J.; Rosenbaum, H.; Baumann, N.; MacKenzie, J. J.; Simon,
Z.; Aharon-Peretz, J.; Walker, J. M.: Gaucher disease associated
with parkinsonism: four further case reports. Am. J. Med. Genet. 116A:
348-351, 2003.

123. Vaughan, J. R.; Davis, M. B.; Wood, N. W.: Genetics of parkinsonism:
a review. Ann. Hum. Genet. 65: 111-126, 2001.

124. Vilarino-Guell, C.; Wider, C.; Aasly, J. O.; White, L. R.; Rajput,
A.; Rajput, A. H.; Lynch, T.; Krygowska-Wajs, A.; Jasinska-Myga, B.;
Opala, G.; Barcikowska, M.; Czyzewski, K.; Wu, R.-M.; Uitti, R. J.;
Wszolek, Z. K.; Farrer, M. J.; Ross, O. A.: Association of pyridoxal
kinase and Parkinson disease. Ann. Neurol. 67: 409-411, 2010.

125. Voon, V.; Thomsen, T.; Miyasaki, J. M.; de Souza, M.; Shafro,
A.; Fox, S. H.; Duff-Canning, S.; Lang, A. E.; Zurowski, M.: Factors
associated with dopaminergic drug-related pathological gambling in
Parkinson disease. Arch. Neurol. 64: 212-216, 2007.

126. Ward, C. D.; Duvoisin, R. C.; Ince, S. E.; Nutt, J. D.; Eldridge,
R.; Calne, D. B.: Parkinson's disease in 65 pairs of twins and in
a set of quadruplets. Neurology 33: 815-824, 1983.

127. Warner, T. T.; Schapira, A. H. V.: Genetic and environmental
factors in the cause of Parkinson's disease. Ann. Neurol. 53 (suppl.
3): S16-S25, 2003.

128. West, A. B.; Maraganore, D.; Crook, J.; Lesnick, T.; Lockhart,
P. J.; Wilkes, K. M.; Kapatos, G.; Hardy, J. A.; Farrer, M. J.: Functional
association of the parkin gene promoter with idiopathic Parkinson's
disease. Hum. Molec. Genet. 11: 2787-2792, 2002.

129. Wirdefeldt, K.; Gatz, M.; Schalling, M.; Pedersen, N. L.: No
evidence for heritability of Parkinson disease in Swedish twins. Neurology 63:
305-311, 2004.

130. Wu, R. M.; Cheng, C. W.; Chen, K. H.; Lu, S. L.; Shan, D. E.;
Ho, Y. F.; Chern, H. D.: The COMT L allele modifies the association
between MAOB polymorphism and PD in Taiwanese. Neurology 56: 375-382,
2001.

131. Young, W. I.; Martin, W. E.; Anderson, E.: The distribution
of ancestral secondary cases in Parkinson's disease. Clin. Genet. 11:
189-192, 1977.

132. Zareparsi, S.; Taylor, T. D.; Harris, E. L.; Payami, H.: Segregation
analysis of Parkinson disease. Am. J. Med. Genet. 80: 410-417, 1998.

133. Zhang, Z.-X.; Dong, Z.-H.; Roman, G. C.: Early descriptions
of Parkinson disease in ancient China. Arch. Neurol. 63: 782-784,
2006.

*FIELD* CS
INHERITANCE:
Isolated cases;
Multifactorial

HEAD AND NECK:
[Face];
Masked facies;
[Nose];
Decreased sense of smell

GENITOURINARY:
[Bladder];
Urinary urgency

ABDOMEN:
[Gastrointestinal];
Dysphagia;
Constipation

NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Bradykinesia;
Rigidity;
Postural instability;
Resting tremor;
Micrographia;
Gait disturbances;
Shuffling gait;
Dystonia;
Dysarthria;
Monotonous speech;
Dysautonomia may occur;
Visual hallucinations may occur;
Dementia may occur;
Sleep disturbances;
Neuronal loss and gliosis in the substantia nigra pars compacta;
Loss of dopaminergic neurons;
Intracellular Lewy bodies;
Aggregation of SNCA-immunopositive inclusions;
[Behavioral/psychiatric manifestations];
Depression

MISCELLANEOUS:
Onset mid to late adulthood;
Insidious onset;
Progressive disorder;
Levodopa-responsive

*FIELD* CN
Cassandra L. Kniffin - revised: 11/15/2010

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 06/27/2012
ckniffin: 11/15/2010

*FIELD* CN
Ada Hamosh - updated: 12/06/2013
Cassandra L. Kniffin - updated: 3/7/2013
Cassandra L. Kniffin - updated: 12/4/2012
Cassandra L. Kniffin - updated: 3/21/2012
Cassandra L. Kniffin - updated: 9/6/2011
Cassandra L. Kniffin - updated: 6/23/2011
Cassandra L. Kniffin - updated: 3/24/2011
Cassandra L. Kniffin - updated: 11/2/2010
Cassandra L. Kniffin - updated: 9/17/2010
Ada Hamosh - updated: 8/24/2010
Cassandra L. Kniffin - updated: 6/25/2010
Cassandra L. Kniffin - updated: 5/6/2010
Cassandra L. Kniffin - updated: 3/1/2010
Cassandra L. Kniffin - updated: 2/19/2010
Cassandra L. Kniffin - updated: 11/4/2009
Cassandra L. Kniffin - updated: 10/22/2009
Ada Hamosh - updated: 8/25/2009
Cassandra L. Kniffin - updated: 2/3/2009
Cassandra L. Kniffin - updated: 10/8/2008
Cassandra L. Kniffin - updated: 4/2/2008
Victor A. McKusick - updated: 3/31/2008
Cassandra L. Kniffin - updated: 2/5/2008
Cassandra L. Kniffin - updated: 11/13/2007
Cassandra L. Kniffin - updated: 10/2/2007
Cassandra L. Kniffin - updated: 9/11/2007
Ada Hamosh - updated: 8/17/2007
Cassandra L. Kniffin - updated: 7/17/2007
Ada Hamosh - updated: 2/27/2007
Cassandra L. Kniffin - updated: 2/19/2007
Ada Hamosh - updated: 11/28/2006
Victor A. McKusick - updated: 6/1/2006
Cassandra L. Kniffin - updated: 5/24/2006
Cassandra L. Kniffin - updated: 5/15/2006
Cassandra L. Kniffin - updated: 4/20/2006
Paul J. Converse - updated: 4/5/2006
George E. Tiller - updated: 1/10/2006
Victor A. McKusick - updated: 10/14/2005
George E. Tiller - updated: 10/3/2005
George E. Tiller - updated: 9/12/2005
Cassandra L. Kniffin - updated: 8/26/2005
Ada Hamosh - updated: 7/20/2005
Cassandra L. Kniffin - updated: 4/18/2005
Victor A. McKusick - updated: 11/15/2004
George E. Tiller - updated: 10/27/2004
George E. Tiller - updated: 2/16/2004
Cassandra L. Kniffin - updated: 1/5/2004
Cassandra L. Kniffin - updated: 10/31/2003
Victor A. McKusick - updated: 6/13/2003
Cassandra L. Kniffin - updated: 5/28/2003
Ada Hamosh - updated: 5/9/2003
Victor A. McKusick - updated: 4/11/2003
Victor A. McKusick - updated: 4/9/2003
Ada Hamosh - updated: 3/31/2003
Cassandra L. Kniffin - reorganized: 10/29/2002
Cassandra L. Kniffin - updated: 10/11/2002
Victor A. McKusick - updated: 9/12/2002
Cassandra L. Kniffin - updated: 7/29/2002
Victor A. McKusick - updated: 6/4/2002
Victor A. McKusick - updated: 5/22/2002
Victor A. McKusick - updated: 4/8/2002
Ada Hamosh - updated: 2/6/2002
Victor A. McKusick - updated: 9/27/2001
Victor A. McKusick - updated: 6/26/2001
Victor A. McKusick - updated: 1/4/2001
Ada Hamosh - updated: 11/7/2000
Ada Hamosh - updated: 7/13/2000
Victor A. McKusick - updated: 12/22/1999
Orest Hurko - updated: 6/14/1999
Victor A. McKusick - updated: 12/30/1998
Victor A. McKusick - updated: 4/7/1998
Victor A. McKusick - updated: 2/11/1998
Victor A. McKusick - updated: 9/5/1997
Victor A. McKusick - updated: 6/27/1997
Victor A. McKusick - updated: 3/12/1997
Orest Hurko - updated: 11/6/1996
Orest Hurko - updated: 11/5/1996
Orest Hurko - updated: 4/1/1996
Orest Hurko - updated: 3/6/1996
Orest Hurko - updated: 2/5/1996
Orest Hurko - updated: 11/16/1995

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 12/06/2013
carol: 11/21/2013
ckniffin: 11/19/2013
carol: 4/1/2013
carol: 3/12/2013
ckniffin: 3/7/2013
alopez: 12/13/2012
carol: 12/5/2012
ckniffin: 12/4/2012
terry: 9/25/2012
terry: 8/8/2012
terry: 6/4/2012
terry: 5/17/2012
terry: 4/10/2012
carol: 3/22/2012
ckniffin: 3/21/2012
terry: 10/10/2011
carol: 10/3/2011
ckniffin: 10/3/2011
carol: 9/6/2011
ckniffin: 9/6/2011
ckniffin: 9/1/2011
wwang: 6/29/2011
ckniffin: 6/23/2011
wwang: 4/13/2011
wwang: 4/12/2011
ckniffin: 3/24/2011
carol: 1/28/2011
ckniffin: 11/17/2010
alopez: 11/10/2010
wwang: 11/2/2010
wwang: 9/23/2010
ckniffin: 9/17/2010
mgross: 8/24/2010
terry: 8/24/2010
wwang: 8/4/2010
wwang: 7/14/2010
ckniffin: 6/25/2010
carol: 5/25/2010
wwang: 5/10/2010
ckniffin: 5/6/2010
wwang: 3/4/2010
ckniffin: 3/1/2010
wwang: 2/19/2010
ckniffin: 2/19/2010
alopez: 1/4/2010
wwang: 12/28/2009
terry: 12/1/2009
carol: 11/11/2009
ckniffin: 11/4/2009
wwang: 10/30/2009
ckniffin: 10/22/2009
carol: 9/4/2009
alopez: 9/1/2009
terry: 8/25/2009
wwang: 2/9/2009
terry: 2/6/2009
ckniffin: 2/3/2009
ckniffin: 10/17/2008
wwang: 10/15/2008
ckniffin: 10/8/2008
carol: 9/29/2008
ckniffin: 9/29/2008
carol: 9/25/2008
mgross: 7/17/2008
ckniffin: 4/30/2008
wwang: 4/10/2008
ckniffin: 4/2/2008
alopez: 4/1/2008
terry: 3/31/2008
wwang: 2/11/2008
ckniffin: 2/5/2008
wwang: 2/4/2008
ckniffin: 11/13/2007
alopez: 11/7/2007
wwang: 10/8/2007
ckniffin: 10/2/2007
wwang: 9/12/2007
ckniffin: 9/11/2007
carol: 8/17/2007
ckniffin: 7/17/2007
alopez: 3/8/2007
terry: 2/27/2007
wwang: 2/22/2007
ckniffin: 2/19/2007
alopez: 12/7/2006
terry: 11/28/2006
alopez: 8/4/2006
alopez: 6/1/2006
wwang: 5/24/2006
ckniffin: 5/24/2006
ckniffin: 5/15/2006
wwang: 4/26/2006
ckniffin: 4/20/2006
mgross: 4/5/2006
wwang: 2/15/2006
terry: 1/10/2006
terry: 12/21/2005
alopez: 10/18/2005
alopez: 10/17/2005
terry: 10/14/2005
wwang: 10/4/2005
alopez: 10/3/2005
terry: 9/12/2005
wwang: 9/6/2005
ckniffin: 8/26/2005
alopez: 7/20/2005
terry: 7/20/2005
wwang: 5/3/2005
ckniffin: 4/18/2005
carol: 4/18/2005
tkritzer: 11/18/2004
terry: 11/15/2004
tkritzer: 10/27/2004
carol: 9/21/2004
alopez: 6/17/2004
cwells: 2/16/2004
tkritzer: 1/7/2004
ckniffin: 1/5/2004
carol: 11/11/2003
tkritzer: 11/6/2003
ckniffin: 10/31/2003
tkritzer: 9/17/2003
tkritzer: 9/15/2003
alopez: 6/23/2003
terry: 6/13/2003
carol: 6/6/2003
carol: 5/28/2003
ckniffin: 5/27/2003
alopez: 5/16/2003
cwells: 5/12/2003
terry: 5/9/2003
ckniffin: 4/15/2003
carol: 4/14/2003
terry: 4/11/2003
carol: 4/9/2003
terry: 4/9/2003
alopez: 4/1/2003
terry: 3/31/2003
carol: 1/16/2003
carol: 10/29/2002
ckniffin: 10/17/2002
carol: 10/14/2002
ckniffin: 10/11/2002
carol: 9/19/2002
tkritzer: 9/12/2002
carol: 9/9/2002
carol: 8/7/2002
ckniffin: 7/29/2002
alopez: 6/13/2002
alopez: 6/12/2002
cwells: 6/12/2002
terry: 6/4/2002
cwells: 6/4/2002
cwells: 6/3/2002
terry: 5/22/2002
cwells: 4/19/2002
carol: 4/19/2002
cwells: 4/17/2002
terry: 4/8/2002
carol: 4/2/2002
alopez: 2/7/2002
terry: 2/6/2002
alopez: 9/28/2001
terry: 9/27/2001
mcapotos: 7/2/2001
mcapotos: 6/28/2001
terry: 6/26/2001
mgross: 5/18/2001
cwells: 1/11/2001
cwells: 1/10/2001
terry: 1/4/2001
carol: 11/17/2000
mgross: 11/7/2000
terry: 11/7/2000
carol: 11/6/2000
terry: 10/6/2000
alopez: 7/13/2000
mcapotos: 1/4/2000
terry: 12/22/1999
carol: 6/14/1999
carol: 1/4/1999
terry: 12/30/1998
carol: 11/23/1998
carol: 6/10/1998
carol: 5/2/1998
terry: 4/7/1998
alopez: 2/11/1998
dholmes: 2/6/1998
terry: 9/12/1997
terry: 9/5/1997
alopez: 7/7/1997
mark: 6/27/1997
terry: 6/27/1997
terry: 3/12/1997
terry: 3/6/1997
terry: 2/10/1997
mark: 1/6/1997
mark: 11/15/1996
terry: 11/15/1996
mark: 11/6/1996
terry: 10/22/1996
terry: 4/15/1996
mark: 4/2/1996
terry: 4/1/1996
terry: 3/22/1996
mark: 3/6/1996
terry: 2/29/1996
mark: 2/5/1996
terry: 1/31/1996
mark: 9/13/1995
terry: 7/28/1995
mimadm: 3/25/1995
carol: 1/19/1995
jason: 6/27/1994

MIM 168601
*RECORD*
*FIELD* NO
168601
*FIELD* TI
#168601 PARKINSON DISEASE 1, AUTOSOMAL DOMINANT; PARK1
PARKINSON DISEASE 1, AUTOSOMAL DOMINANT LEWY BODY;;
read moreATYPICAL PARKINSON DISEASE, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because evidence shows that
this form of Parkinson disease (PARK1) is caused by mutation in the
alpha-synuclein gene (SNCA; 163890) on chromosome 4q22.1.

See also dementia with Lewy bodies (127750), an allelic disorder with
overlapping clinical features.

DESCRIPTION

Parkinson disease is the second most common neurogenic disorder after
Alzheimer disease (AD; 104300), affecting approximately 1% of the
population over age 50. Clinical manifestations include resting tremor,
muscular rigidity, bradykinesia, and postural instability. Additional
features are characteristic postural abnormalities, dysautonomia,
dystonic cramps, and dementia (Polymeropoulos et al., 1996).

For a general phenotypic description and a discussion of genetic
heterogeneity of Parkinson disease, see 168600.

CLINICAL FEATURES

Golbe et al. (1990) reported 2 large kindreds originating from Contursi,
a village in the Salerno province of Italy, in which 41 individuals in 4
generations had autosomal dominant Parkinson disease. Male-to-male
transmission occurred, and penetrance was estimated at 96%; only 1
instance of definite nonpenetrance was recognized. The disorder was
characterized by early onset (mean 46.5 years) and rapid progression
(average 9.7 years from onset to death). Clinical appearance and
response to levodopa were typical for Parkinson disease. Autopsy of 2
patients in 1 of the kindreds showed pathologic changes typical of PD
with Lewy bodies. Affected persons who spent most of their lives in
Italy survived longer than their affected U.S. relatives. Golbe et al.
(1990) postulated a single gene as the main factor in these kindreds and
concluded that the findings enhanced the likelihood of a significant
genetic component in sporadic PD. In a follow-up study of these
kindreds, Golbe et al. (1996) found 60 affected individuals in 5
generations. There was variation in clinical features regarding age of
onset, tremor, and levodopa responsiveness, suggesting that a presumably
single mutation can produce a heterogeneous PD phenotype, even among
sibs. A suggestion of anticipation disappeared after adjustment for
age-related ascertainment bias.

Spira et al. (2001) reported a family of Greek origin with 5 of 9 sibs
affected with PD, 3 of whom were examined in detail and were found to
carry a mutation in the SNCA gene (163890.0001). The 3 sibs presented in
their forties with progressive bradykinesia and rigidity, which was
initially dopa-responsive, and cognitive decline. Additional features
included central hypoventilation, postural hypotension, bladder
incontinence, and myoclonus.

Puschmann et al. (2009) reported 2 affected members of a Swedish family
with the SNCA A53T mutation (163890.0001). Haplotype analysis indicated
a different haplotype than the previously identified Greek founder
haplotype, suggesting a de novo event in this Swedish family. The
proband had insidious onset of decreased range of motion, stiffness, and
hypokinesia between ages 39 and 41 years. About 6 months later, she
developed word-finding difficulty and monotone speech. The disorder was
progressive, and by age 47, she had developed dementia and severe motor
disturbances, including myoclonus. Her father developed motor signs of
the disorder at age 32, with speech difficulties at age 33. At age 38,
he was moved to a nursing home, and at 40, he was aphonic with dementia
and an inability to walk or feed himself independently. Both patients
had an initial favorable response to levodopa treatment. Both patients
had normal brain MRI and increased CSF protein levels, and SPECT scan of
the daughter showed decreased blood flow in the language region.
Puschmann et al. (2009) emphasized the early onset, rapid progression,
and presence of dementia in this family with PD, and suggested that an
underlying cortical encephalopathy contributed to the disease course.

- Clinical Variability

Golbe et al. (1993) described a family with very slowly progressive
atypical autosomal dominant Parkinson disease that showed, in most
affected members, poor response to levodopa and subjective visual
difficulty. Four cases in 3 generations had onset of symptoms at age 35,
25, 16, and 16, and 4 suspicious cases had occurred in 3 other
generations. There seemed to be a trend toward progressively earlier age
of onset. One autopsied case showed a distribution of cell loss and Lewy
bodies typical of PD. Golbe et al. (1993) noted several previously
described kindreds with clinically atypical autosomal dominant PD,
including a report by Inose et al. (1988).

Lesage et al. (2013) reported a French family in which 4 individuals had
a disorder comprising rapidly progressive Parkinson disease, pyramidal
signs, and psychiatric features. Three affected individuals had onset at
age 31 to 35 years, whereas the fourth had onset at age 60. The initial
symptoms were parkinsonism with moderate response to levodopa and
development of levodopa-induced dyskinesia. All also had pyramidal tract
involvement, with hyperreflexia and extensor plantar responses; 1 had
severe spasticity. Two patients had marked psychiatric manifestations,
including hallucinations, delusions, anxiety, and depression, but not
dementia. The disorder was rapidly progressive: all became bedridden
within 5 to 7 years, and 3 patients died within 5 to 7 years of onset.
Neuropathologic examination of 1 patient showed neuronal loss in the
substantia nigra and striatum, as well as astrogliosis. There was also
neuronal loss in the motor cortex, the anterior horn of the spinal cord,
and the corticospinal tracts. Lewy bodies and dystrophic Lewy neurites
were present mostly in the brainstem. There were fine, diffuse, neuronal
cytoplasmic inclusions in all superficial cortical layers.

- Pathologic Findings

In Parkinson disease, the specific pattern of neuronal degeneration is
accompanied by eosinophilic intracytoplasmic inclusions known as Lewy
bodies in surviving neurons in the substantia nigra, locus ceruleus,
nucleus basalis, cranial nerve motor nuclei, central and peripheral
divisions of the autonomic nervous system, hypothalamus, and cerebral
cortex (Polymeropoulos et al., 1996).

Neuropathologic examination of 2 of the 5 sibs with PD reported by Spira
et al. (2001) showed depigmentation of the substantia nigra, severe cell
loss and gliosis in the brainstem, and multiple
alpha-synuclein-immunopositive Lewy neurites. Cortical neuritic changes
associated with tissue vacuolization were present, mostly in the medial
temporal regions.

Seidel et al. (2010) reported neuropathologic findings of a patient with
PD due to the SNCA A30P mutation (163890.0002). He had onset at age 54
years, had L-dopa-related complications, and died in a mute, bedridden
state at age 69. Progressive cognitive decline was also reported.
Postmortem examination showed depigmentation and neuronal loss in the
substantia nigra and neuronal loss in the locus ceruleus and dorsal
motor vagal nucleus. There were widespread SNCA-positive Lewy bodies,
Lewy neurites, and glial aggregates in the cerebral cortex and many
other regions of the brain, including the hippocampus, hypothalamus,
brainstem, and cerebellum. Biochemical analysis showed a significant
load of insoluble SNCA. The findings were similar to, but more severe,
than those observed in idiopathic PD.

INHERITANCE

The transmission pattern in the families with PARK1 reported by Golbe et
al. (1990) and Lesage et al. (2013) was consistent with autosomal
dominant inheritance.

MAPPING

Polymeropoulos et al. (1996) performed a genomewide linkage scan in the
large Italian kindred previously reported by Golbe et al. (1990).
Linkage to markers in the 4q21-q23 region was found with a maximum lod
score of 6.00 at recombination fraction theta = 0.00 for marker D4S2380.

In a genomewide association study and 2 replication studies in a total
of 2,011 cases and 18,381 controls from Japan, Satake et al. (2009)
found strong association with the SNCA gene (163890) on 4q22.1 (p = 7.35
x 10(-17)), implicated in PARK1. In a genomewide association study in
1,713 individuals of European ancestry with PD and 3,978 controls,
followed by replication in 3,361 cases and 4,573 controls, Simon-Sanchez
et al. (2009) identified association with the SNCA gene (dbSNP
rs2736990, OR = 1.23, p = 2.24 x 10(-16)).

MOLECULAR GENETICS

In the Italian kindred first reported by Golbe et al. (1990) and in 3
unrelated families of Greek origin with autosomal dominant inheritance
of Parkinson disease, Polymeropoulos et al. (1997) identified a
heterozygous mutation in the SNCA gene (A53T; 163890.0001), which
encodes a presynaptic protein thought to be involved in neuronal
plasticity.

Duvoisin and Golbe (1995) reviewed the genetics of parkinsonism with
Lewy body pathology, which they considered to be 'true' Parkinson
disease.

In 4 members of a French family with autosomal dominant PD, pyramidal
signs, and psychiatric abnormalities, Lesage et al. (2013) identified a
heterozygous missense mutation in the SNCA gene (G51D; 163890.0006). The
mutation, which was found by whole-exome sequencing and confirmed by
Sanger sequencing, segregated with the disorder in the family.
Functional studies showed that the mutant protein oligomerized more
slowly than wildtype, but that its fibrils conferred significant
cellular toxicity.

- SNCA Gene Duplication

Nishioka et al. (2006) identified heterozygosity for duplication of the
SNCA gene (163890.0005) in 2 of 113 Japanese probands with autosomal
dominant PD. In the first family, 2 patients with the duplication had
typical PD, whereas 4 duplication carriers over the age of 43 years were
unaffected, yielding a penetrance of 33%. In the second family, 1
affected and 2 asymptomatic members had the duplication. The affected
patient from the second family developed dementia 14 years after
diagnosis of PD, consistent with Lewy body dementia.

Fuchs et al. (2007) reported a Swedish family with parkinsonism due to
duplication of the SNCA gene. The proband presented with dysautonomia
followed by rapidly progressive parkinsonism. Family history revealed
multiple affected members with a similar disorder. Features of dementia,
including hallucinations, occurred late in the disease. This family was
determined to be a branch of a large family originally reported by
Mjones (1949). A Swedish American branch of that family was found by
Farrer et al. (2004) to have a triplication of the SNCA gene
(163890.0003). Fuchs et al. (2007) found that genotypes within and
flanking the duplicated region in the Swedish family were identical to
genotypes in the Swedish American family reported by Farrer et al.
(2004), suggesting a common founder. Hybridization signals indicated a
tandem multiplication of the same genomic interval in the 2 families, a
duplication and triplication, respectively. Sequence analysis indicated
that the multiplications were mediated by centromeric and telomeric long
interspersed nuclear element (LINE L1) motifs.

Brueggemann et al. (2008) and Troiano et al. (2008) independently
identified duplications of the SNCA gene in 2 patients with sporadic
early-onset PD, at ages 36 and 35 years, respectively. The mutation was
confirmed to be de novo in the case of Brueggemann et al. (2008).
Neither patient had cognitive impairment. The prevalence of the SNCA
duplication in sporadic PD was reported to be 0.25 and 1%, respectively.

PATHOGENESIS

Lotharius and Brundin (2002) reviewed the literature on SNCA and
suggested a possible role for this protein in vesicle recycling via its
regulation of phospholipase D2 and its fatty acid-binding properties.
They hypothesized that impaired neurotransmitter storage arising from
SNCA mutations could lead to cytoplasmic accumulation of dopamine,
resulting in breakdown of this labile neurotransmitter in the cytoplasm
and promoting oxidative stress and metabolic dysfunction in the
substantia nigra.

Kazantsev and Kolchinsky (2008) reviewed current concepts on the
pathogenesis of PD and noted that the symptoms result from acute
shortage of dopamine due to selective loss of dopaminergic neurons in
the substantia nigra. The metabolism of dopamine yields toxic
derivatives that are normally polymerized to form dark nontoxic
neuromelanin, which is deposited in the cells. The lack of pigmentation
in PD substantia nigra may reflect an inability to process these toxic
metabolites. These findings support a role for reactive oxygen species
(ROS) in PD. The presence of SNCA-containing Lewy bodies implicates
protein misfolding as a pathogenic event that disrupts normal cellular
function.

CLINICAL MANAGEMENT

Using unbiased phenotypic screens as an alternative to target-based
approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole
(NAB) that strongly and selectively protected diverse cell types from
alpha-synuclein toxicity. Three chemical genetic screens in wildtype
yeast cells established that NAB promoted endosomal transport events
dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These same
steps were perturbed by alpha-synuclein itself. Tardiff et al. (2013)
concluded that NAB identifies a druggable node in the biology of
alpha-synuclein that can correct multiple aspects of its underlying
pathology, including dysfunctional endosomal and endoplasmic
reticulum-to-Golgi-vesicle trafficking.

Chung et al. (2013) exploited mutation correction of iPS cells and
conserved proteotoxic mechanisms from yeast to humans to discover and
reverse phenotypic responses to alpha-synuclein (163890), a key protein
involved in Parkinson disease. Chung et al. (2013) generated cortical
neurons from iPS cells of patients harboring alpha-synuclein mutations
(A53T; 163890.0001), who are at high risk of developing PD dementia.
Genetic modifiers from unbiased screens in a yeast model of
alpha-synuclein toxicity led to identification of early pathogenic
phenotypes in patient neurons, including nitrosative stress,
accumulation of endoplasmic reticulum-associated degradation substrates,
and ER stress. A small molecule, NAB2, identified in a yeast screen, and
NEDD4, the ubiquitin ligase that it affects, reversed pathologic
phenotypes in these neurons.

ANIMAL MODEL

To determine if SNCA lesions lead to neurodegeneration, Giasson et al.
(2002) generated transgenic mice expressing the A53T mutation
(163890.0001) in CNS neurons. Mice expressing the A53T mutant developed
a severe and complex motor impairment leading to paralysis and death.
The animals developed age-dependent intracytoplasmic neuronal SNCA
inclusions paralleling disease onset, and the inclusions recapitulated
features of human counterparts. Using immunoelectron microscopy, Giasson
et al. (2002) revealed that the SNCA inclusions in the mutant mice
contained fibrils similar to human pathologic inclusions. The authors
concluded that A53T leads to the formation of toxic filamentous SNCA
neuronal inclusions that cause neurodegeneration.

Kuo et al. (2010) developed transgenic mice expressing mutant
alpha-synuclein, either A53T (163890.0001) or A30P (163890.0002), from
insertions of an entire human SNCA gene as models for the familial
disease. Both the A53T and A30P lines showed abnormalities in enteric
nervous system (ENS) function and synuclein-immunoreactive aggregates in
ENS ganglia by 3 months of age. The A53T line also had abnormal motor
behavior, but neither line demonstrated cardiac autonomic abnormalities,
olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body
inclusions, or neurodegeneration. These animals recapitulated the early
gastrointestinal abnormalities seen in human Parkinson disease.

*FIELD* RF
1. Brueggemann, N.; Odin, P.; Gruenewald, A.; Tadic, V.; Hagenah,
J.; Seidel, G.; Lohmann, K.; Klein, C.; Djarmati, A.: Alpha-synuclein
gene duplication is present in sporadic Parkinson disease. Neurology 71:
1294 only, 2008.

2. Chung, C. Y.; Khurana, V.; Auluck, P. K.; Tardiff, D. F.; Mazzulli,
J. R.; Soldner, F.; Baru, V.; Lou, Y.; Freyzon, Y.; Cho, S.; Mungenast,
A. E.; Muffat, J.; and 10 others: Identification and rescue of
alpha-synuclein toxicity in Parkinson patient-derived neurons. Science 342:
983-987, 2013.

3. Duvoisin, R. C.; Golbe, L. I.: Kindreds of dominantly inherited
Parkinson's disease: keys to the riddle. Ann. Neurol. 38: 355-356,
1995.

4. Farrer, M.; Kachergus, J.; Forno, L.; Lincoln, S.; Wang, D.-S.;
Hulihan, M.; Maraganore, D.; Gwinn-Hardy, K.; Wszolek, Z.; Dickson,
D.; Langston, J. W.: Comparison of kindreds with parkinsonism and
alpha-synuclein genomic multiplications. Ann. Neurol. 55: 174-179,
2004.

5. Fuchs, J.; Nilsson, C.; Kachergus, J.; Munz, M.; Larsson, E.-M.;
Schule, B.; Langston, J. W.; Middleton, F. A.; Ross, O. A.; Hulihan,
M.; Gasser, T.; Farrer, M. J.: Phenotypic variation in a large Swedish
pedigree due to SNCA duplication and triplication. Neurology 68:
916-922, 2007.

6. Giasson, B. I.; Duda, J. E.; Quinn, S. M.; Zhang, B.; Trojanowski,
J. Q.; Lee, V. M.-Y.: Neuronal alpha-synucleinopathy with severe
movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:
521-533, 2002.

7. Golbe, L. I.; Di Iorio, G.; Bonavita, V.; Miller, D. C.; Duvoisin,
R. C.: A large kindred with autosomal dominant Parkinson's disease. Ann.
Neurol. 27: 276-282, 1990.

8. Golbe, L. I.; Di Iorio, G.; Sanges, G.; Lazzarini, A. M.; La Sala,
S.; Bonavita, V.; Duvoisin, R. C.: Clinical genetic analysis of Parkinson's
disease in the Contursi kindred. Ann. Neurol. 40: 767-775, 1996.

9. Golbe, L. I.; Lazzarini, A. M.; Schwarz, K. O.; Mark, M. H.; Dickson,
D. W.; Duvoisin, R. C.: Autosomal dominant parkinsonism with benign
course and typical Lewy-body pathology. Neurology 43: 2222-2227,
1993.

10. Inose, T.; Miyakawa, M.; Miyakawa, K.; Mizushima, S.; Oyanagi,
S.; Ando, S.: Clinical and neuropathological study of a familial
case of juvenile parkinsonism. Jpn. J. Psychiat. Neurol. 42: 265-276,
1988.

11. Kazantsev, A. G.; Kolchinsky, A. M.: Central role of alpha-synuclein
oligomers in neurodegeneration in Parkinson disease. Arch. Neurol. 65:
1577-1581, 2008.

12. Kuo, Y.-M.; Li, Z.; Jiao, Y.; Gaborit, N.; Pani, A. K.; Orrison,
B. M.; Bruneau, B. G.; Giasson, B. I.; Smeyne, R. J.; Gershon, M.
D.; Nussbaum, R. L.: Extensive enteric nervous system abnormalities
in mice transgenic for artificial chromosomes containing Parkinson
disease-associated alpha-synuclein gene mutations precede central
nervous system changes. Hum. Molec. Genet. 19: 1633-1650, 2010.

13. Lesage, S.; Anheim, M.; Letournel, F.; Bousset, L.; Honore, A.;
Rozas, N.; Pieri, L.; Madiona, K.; Durr, A.; Melki, R.; Verny, C.;
Brice, A.: G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal
syndrome. Ann. Neurol. 73: 459-471, 2013.

14. Lotharius, J.; Brundin, P.: Impaired dopamine storage resulting
from alpha-synuclein mutations may contribute to the pathogenesis
of Parkinson's disease. Hum. Molec. Genet. 11: 2395-2407, 2002.

15. Mjones, H.: Paralysis agitans: a clinical and genetic study. Acta
Psychiat. Neurol. 54: 1-195, 1949.

16. Nishioka, K.; Hayashi, S.; Farrer, M. J.; Singleton, A. B.; Yoshino,
H.; Imai, H.; Kitami, T.; Sato, K.; Kuroda, R.; Tomiyama, H.; Mizoguchi,
K.; Murata, M.; Toda, T.; Imoto, I.; Inazawa, J.; Mizuno, Y.; Hattori,
N.: Clinical heterogeneity of alpha-synuclein gene duplication in
Parkinson's disease. Ann. Neurol. 59: 298-309, 2006.

17. Polymeropoulos, M. H.; Higgins, J. J.; Golbe, L. I.; Johnson,
W. G.; Ide, S. E.; Di Iorio, G.; Sanges, G.; Stenroos, E. S.; Pho,
L. T.; Schaffer, A. A.; Lazzarini, A. M.; Nussbaum, R. L.; Duvoisin,
R. C.: Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 274:
1197-1198, 1996.

18. Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.; Dehejia,
A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; Stenroos,
E. S.; Chandrasekharappa, S.; Athanassiadou, A.; Papepetropoulos,
T.; Johnson, W. G.; Lazzarini, A. M.; Duvoisin, R. C.; Di Iorio, G.;
Golbe, L. I.; Nussbaum, R. L.: Mutation in the alpha-synuclein gene
identified in families with Parkinson's disease. Science 276: 2045-2047,
1997.

19. Puschmann, A.; Ross, O. A.; Vilarino-Guell, C.; Lincoln, S. J.;
Kachergus, J. M.; Cobb, S. A.; Lindquist, S. G.; Nielsen, J. E.; Wszolek,
Z. K.; Farrer, M.; Widner, H.; van Westen, D.; Hagerstrom, D.; Markopoulou,
K.; Chase, B. A.; Nilsson, K.; Reimer, J.; Nilsson, C.: A Swedish
family with de novo alpha-synuclein A53T mutation: evidence for early
cortical dysfunction. Parkinson. Relat. Disord. 15: 627-632, 2009.

20. Satake, W.; Nakabayashi, Y.; Mizuta, I.; Hirota, Y.; Ito, C.;
Kubo, M.; Kawaguchi, T.; Tsunoda, T.; Watanabe, M.; Takeda, A.; Tomiyama,
H.; Nakashima, K.; and 10 others: Genome-wide association study
identifies common variants at four loci as genetic risk factors for
Parkinson's disease. (Letter) Nature Genet. 41: 1303-1307, 2009.

21. Seidel, K.; Schols, L.; Nuber, S.; Petrasch-Parwez, E.; Gierga,
K.; Wszolek, Z.; Dickson, D.; Gai, W. P.; Bornemann, A.; Riess, O.;
Rami, A.; den Dunnen, W. F. A.; Deller, T.; Rub, U.; Kruger, R.:
First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann.
Neurol. 67: 684-689, 2010. Note: Erratum: Ann. Neurol. 67: 841 only,
2010.

22. Simon-Sanchez, J.; Schulte, C.; Bras, J. M.; Sharma, M.; Gibbs,
J. R.; Berg, D.; Paisan-Ruiz, C.; Lichtner, P.; Scholz, S. W.; Hernandez,
D. G.; Kruger, R.; Federoff, M.; and 35 others: Genome-wide association
study reveals genetic risk underlying Parkinson's disease. (Letter) Nature
Genet. 41: 1308-1312, 2009.

23. Spira, P. J.; Sharpe, D. M.; Halliday, G.; Cavanagh, J.; Nicholson,
G. A.: Clinical and pathological features of a Parkinsonian syndrome
in a family with an ala53-to-thr alpha-synuclein mutation. Ann. Neurol. 49:
313-319, 2001.

24. Tardiff, D. F.; Jui, N. T.; Khurana, V.; Tambe, M. A.; Thompson,
M. L.; Chung, C. Y.; Kamadurai, H. B.; Kim, H. T.; Lancaster, A. K.;
Caldwell, K. A.; Caldwell, G. A.; Rochet, J.-C.; Buchwald, S. L.;
Lindquist, S.: Yeast reveal a 'druggable' Rsp5/Nedd4 network that
ameliorates alpha-synuclein toxicity in neurons. Science 342: 979-983,
2013.

25. Troiano, A. R.; Cazeneuve, C.; Le Ber, I.; Bonnet, A.-M.; Lesage,
S.; Brice, A.: Alpha-synuclein gene duplication is present in sporadic
Parkinson disease. Neurology 71: 1295 only, 2008.

*FIELD* CN
Cassandra L. Kniffin - updated: 1/29/2014
Ada Hamosh - updated: 12/6/2013
George E. Tiller - updated: 12/2/2011
Cassandra L. Kniffin - updated: 10/25/2010
Cassandra L. Kniffin - updated: 6/17/2010
Cassandra L. Kniffin - updated: 1/4/2010
Cassandra L. Kniffin - updated: 3/27/2009
Cassandra L. Kniffin - updated: 3/17/2009
Cassandra L. Kniffin - updated: 12/18/2007
Cassandra L. Kniffin - updated: 4/20/2006
George E. Tiller - updated: 12/3/2003
Dawn Watkins-Chow - updated: 3/28/2003
Cassandra L. Kniffin - reorganized: 10/29/2002
Ada Hamosh - updated: 1/9/2001
Victor A. McKusick - updated: 2/17/1999
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 2/11/1998
Orest Hurko - updated: 2/5/1996

*FIELD* CD
Victor A. McKusick: 1/13/1995

*FIELD* ED
carol: 02/06/2014
mcolton: 2/4/2014
ckniffin: 1/29/2014
alopez: 12/6/2013
terry: 11/29/2012
terry: 9/24/2012
alopez: 12/2/2011
terry: 12/2/2011
ckniffin: 11/17/2010
ckniffin: 11/16/2010
wwang: 11/1/2010
ckniffin: 10/25/2010
wwang: 8/4/2010
ckniffin: 6/17/2010
alopez: 1/4/2010
carol: 6/23/2009
wwang: 4/7/2009
ckniffin: 3/27/2009
wwang: 3/26/2009
ckniffin: 3/17/2009
ckniffin: 1/9/2009
wwang: 1/7/2008
ckniffin: 12/18/2007
wwang: 4/26/2006
ckniffin: 4/20/2006
terry: 2/22/2005
mgross: 12/3/2003
cwells: 3/28/2003
carol: 12/16/2002
tkritzer: 12/13/2002
ckniffin: 12/9/2002
carol: 10/29/2002
ckniffin: 10/23/2002
ckniffin: 10/22/2002
carol: 1/9/2001
mgross: 2/25/1999
mgross: 2/19/1999
terry: 2/17/1999
carol: 10/18/1998
terry: 10/13/1998
alopez: 2/11/1998
dholmes: 2/6/1998
terry: 4/15/1996
mark: 2/5/1996
terry: 1/31/1996
carol: 1/13/1995

MIM 605543
*RECORD*
*FIELD* NO
605543
*FIELD* TI
#605543 PARKINSON DISEASE 4, AUTOSOMAL DOMINANT; PARK4
;;PARKINSON DISEASE 4, AUTOSOMAL DOMINANT LEWY BODY
read more*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
Parkinson disease-4 (PARK4) is caused by triplication of the
alpha-synuclein gene (SNCA; 163890).

See also PD1 (168601) and Lewy body dementia (DLB; 127750), which are
also caused by mutation in the SNCA gene and show overlapping phenotypes
with PARK4.

For a phenotypic description and a discussion of genetic heterogeneity
of Parkinson disease (PD), see 168600.

CLINICAL FEATURES

Spellman (1962) described a family in which multiple members in 4
generations had autosomal dominant parkinsonism beginning in their
thirties and progressing rapidly to death in 2 to 12 years. This
extended family was of English and German origin and later referred to
as the 'Iowa kindred' (Farrer et al., 2004). Waters and Miller (1994)
and Muenter et al. (1998) later described this same family in greater
detail. The proposita developed parkinsonism at age 45 years and died 6
years later. She had typical features of Parkinson disease except for an
absence of rest tremor, although this was present in other affected
family members. Neuropathologic examination confirmed the diagnosis of
Lewy body parkinsonism. The disorder was characterized by early age at
onset, early weight loss, and rapidly progressive dopa-responsive
parkinsonism, followed by dementia and, in some, by hypotension.
Intellectual dysfunction began with subjective memory loss and objective
visuospatial dysfunction and was followed by decline of frontal lobe
cognitive and memory functions. Neuropathologic examination of autopsied
cases showed neuronal loss in substantial nigra and locus ceruleus and
widespread Lewy bodies, many of them in the cerebral cortex; those in
the hypothalamus and locus ceruleus were often of bizarre shapes. Other
findings were vacuolation of the temporal cortex, unusual neuronal loss,
and gliosis in the hippocampus (CA 2/3), and neuronal loss in the
nucleus basalis. There were no neuritic plaques, neurofibrillary
tangles, or amyloid deposits. Positron emission tomography in 3 patients
showed decreased striatal uptake of fluorodopa. Neurochemical analysis
of an autopsied brain showed a pronounced decrease in choline
acetyltransferase activity in the frontal and temporal cortices and
hippocampus and a severe depletion of striatal dopamine with a pattern
not typical of classic Parkinson disease.

Gwinn-Hardy et al. (2000) reported neuropathologic findings of the
proband from the Iowa kindred. There was striking cortical pathology,
with there were regions of spongiosis and gliosis that were also rich in
many thread-like dystrophic cell processes. These were accompanied by
scattered glial cells with alpha-synuclein-immunoreactive inclusions
somewhat similar to glial cytoplasmic inclusions of multiple system
atrophy. There were also glial inclusions in the cerebral and cerebellar
white matter and in certain white matter fiber tracts, especially in the
basal ganglia and basal forebrain. There were also
alpha-synuclein-immunoreactive round to pleomorphic inclusions within
neurons, mostly in lower cortical layers, but not showing a clear
laminar predilection. The latter inclusions were consistent with
cortical Lewy bodies, and the number and distribution of cortical Lewy
bodies were consistent with neocortical stage of dementia with Lewy
bodies (127750). Immunoblots of brain homogenates using the
alpha-synuclein polyclonal antibody against patients from the Iowa
kindred and normal controls and brains of other synucleinopathies
revealed a 26-kD band and several other high molecular weight species
only in the affected cortex of the Iowa kindred patients. This 26-kD
band was not present in the substantia nigra of the Iowa kindred
patients or of patients with other synucleinopathies. Gwinn-Hardy et al.
(2000) noted that a point mutation in the alpha-synuclein gene had not
been identified in this family.

Farrer et al. (2004) identified a family of Swedish American descent
with autosomal dominant early-onset parkinsonism and dementia due to a
triplication of the SNCA gene. The proband, who had onset at age 31, had
rapidly progressive parkinsonism with tremor, rigidity, and
bradykinesia. At age 45, he developed visual and auditory hallucinations
and paranoia. He also had postural hypotonia. He later developed
intellectual impairment progressing to severe dementia with mutism,
followed by death at age 52 years. Postmortem examination showed severe
neuronal degeneration and loss in the substantia nigra, locus ceruleus,
and hippocampal areas CA 2/3. Lewy bodies were present in the
hypothalamus, basal nucleus of Meynert, and the cerebral cortex. SNCA
mRNA expression was increased compared to controls.

Fuchs et al. (2007) determined that the Swedish American family reported
by Farrer et al. (2004) was part of the Lister family complex originally
described by Mjones (1949). The Swedish American branch of the family
showed early-onset, rapidly progressive parkinsonism associated with
dementia and dysautonomia. Fuchs et al. (2007) identified a Swedish
branch of this extended kindred in which multiple family members had
late-onset parkinsonism and early dysautonomia due to a duplication of
the SNCA gene (163890.0005). Genotypes within and flanking the
duplicated region were identical to genotypes in the Swedish American
family reported by Farrer et al. (2004) and suggested a common founder.
Hybridization signals indicated a tandem multiplication of the same
genomic interval in the 2 families, 1 with duplication and 1 with
triplication. Sequence analysis indicated that the multiplications were
mediated by centromeric and telomeric long interspersed nuclear element
(LINE L1) motifs.

MAPPING

Farrer et al. (1999) suggested that a locus on 4p is responsible for
autosomal dominant Lewy body parkinsonism, and that postural tremor,
consistent with essential tremor (190300), may be an alternate phenotype
of the same pathogenic mutation that causes Lewy body parkinsonism. They
studied the large family described by Waters and Miller (1994) and
Muenter et al. (1998) with levodopa-responsive Lewy body parkinsonism.
After performing a genome screen, they identified a chromosome 4p
haplotype that segregated with the disorder; however, this haplotype
also occurred in individuals in the pedigree who did not have clinical
Lewy body parkinsonism but rather suffered from postural tremor.

In a second genomewide search, Singleton et al. (2003) found a haplotype
cosegregating with the disease over 26 cM, with a multipoint lod score
of 3.50 at marker DS42460 on chromosome 4q.

MOLECULAR GENETICS

By quantitative PCR amplification of SNCA exons in an individual with
parkinsonism from the large family reported by Waters and Miller (1994),
Singleton et al. (2003) found evidence consistent with whole gene
triplication (163890.0003). Analysis of other family members showed that
the SNCA triplication segregated with parkinsonism, but not with
postural tremor. The triplicated region contains an estimated 17 genes,
including SNCA. Carriers of the triplication are predicted to have 4
fully functional copies of SNCA, with doubling of the effective load of
the estimated 17 genes. The authors suggested that increased dosage of
SNCA is the cause of PD in this family. They noted that the disease
process may resemble the etiology of Alzheimer disease (AD; 104300) in
Down syndrome (190685) with overexpression of the APP gene (104760) due
to chromosome 21 trisomy.

Ibanez et al. (2009) identified SNCA gene triplication in 1 (1.5%) of 22
families with atypical PD, including rapid progression and severe
cognitive impairment. Genotyping and dosage analysis indicated that SNCA
multiplications occurred independently. The authors concluded that
alterations in SNCA gene dosage due to rearrangements may be more common
than point mutations.

*FIELD* RF
1. Farrer, M.; Gwinn-Hardy, K.; Muenter, M.; DeVrieze, F. W.; Crook,
R.; Perez-Tur, J.; Lincoln, S.; Maraganore, D.; Adler, C.; Newman,
S.; MacElwee, K.; McCarthy, P.; Miller, C.; Waters, C.; Hardy, J.
: A chromosome 4p haplotype segregating with Parkinson's disease and
postural tremor. Hum. Molec. Genet. 8: 81-85, 1999.

2. Farrer, M.; Kachergus, J.; Forno, L.; Lincoln, S.; Wang, D.-S.;
Hulihan, M.; Maraganore, D.; Gwinn-Hardy, K.; Wszolek, Z.; Dickson,
D.; Langston, J. W.: Comparison of kindreds with parkinsonism and
alpha-synuclein genomic multiplications. Ann. Neurol. 55: 174-179,
2004.

3. Fuchs, J.; Nilsson, C.; Kachergus, J.; Munz, M.; Larsson, E.-M.;
Schule, B.; Langston, J. W.; Middleton, F. A.; Ross, O. A.; Hulihan,
M.; Gasser, T.; Farrer, M. J.: Phenotypic variation in a large Swedish
pedigree due to SNCA duplication and triplication. Neurology 68:
916-922, 2007.

4. Gwinn-Hardy, K.; Mehta, N. D.; Farrer, M.; Maraganore, D.; Muenter,
M.; Yen, S.-H.; Hardy, J.; Dickson, D. W.: Distinctive neuropathology
revealed by alpha-synuclein antibodies in hereditary parkinsonism
and dementia linked to chromosome 4p. Acta Neuropath. 99: 663-672,
2000.

5. Ibanez, P.; Lesage, S.; Janin, S.; Lohmann, E.; Durif, F.; Destee,
A.; Bonnet, A.-M.; Brefel-Courbon, C.; Heath, S.; Zelenika, D.; Agid,
Y.; Durr, A.; Brice, A.: Alpha-synuclein gene rearrangements in dominantly
inherited Parkinsonism. Arch. Neurol. 66: 102-108, 2009.

6. Mjones, H.: Paralysis agitans: a clinical and genetic study. Acta
Psychiat. Neurol. Suppl. 54: 1-195, 1949.

7. Muenter, M. D.; Forno, L. S.; Hornykiewicz, O.; Kish, S. J.; Maraganore,
D. M.; Caselli, R. J.; Okazaki, H.; Howard, F. M., Jr.; Snow, B. J.;
Calne, D. B.: Hereditary form of parkinsonism-dementia. Ann. Neurol. 43:
768-781, 1998.

8. Singleton, A. B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague,
S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum,
R.; Lincoln, S.; Crawley, A.; and 10 others: Alpha-synuclein locus
triplication causes Parkinson's disease. Science 302: 841 only,
2003.

9. Spellman, G. G.: Report of familial cases of parkinsonism: evidence
of a dominant trait in a patient's family. JAMA 179: 372-374, 1962.

10. Waters, C. H.; Miller, C. A.: Autosomal dominant Lewy body parkinsonism
in a four-generation family. Ann. Neurol. 35: 59-64, 1994.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Weight];
Weight loss

CARDIOVASCULAR:
[Vascular];
Hypotension, postural, due to autonomic dysfunction

NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Dementia;
Diffuse Lewy body pathology;
Alpha-synuclein immunoreactive neuronal and glial inclusions;
Autonomic dysfunction;
[Behavioral/psychiatric manifestations];
Hallucinations;
Paranoia

MISCELLANEOUS:
Early age of onset (approximately 45 years);
Rapidly progressive;
Levodopa-responsive;
Phenotype range from typical Parkinson disease (168600) to dementia
with Lewy bodies (127750)

MOLECULAR BASIS:
Caused by triplication of the alpha-synuclein gene (SNCA, 163890.0003)

*FIELD* CN
Cassandra L. Kniffin - updated: 01/16/2008

*FIELD* CD
Cassandra L. Kniffin: 11/11/2002

*FIELD* ED
ckniffin: 01/16/2008
ckniffin: 11/11/2002
joanna: 3/20/2001

*FIELD* CN
Cassandra L. Kniffin - updated: 3/17/2009
Cassandra L. Kniffin - updated: 12/18/2007
Cassandra L. Kniffin - reorganized: 11/11/2003
Cassandra L. Kniffin - updated: 11/10/2003
Cassandra L. Kniffin - updated: 11/7/2003

*FIELD* CD
Ada Hamosh: 1/9/2001

*FIELD* ED
terry: 04/12/2012
ckniffin: 11/17/2010
wwang: 4/7/2009
wwang: 3/26/2009
ckniffin: 3/17/2009
ckniffin: 1/9/2009
carol: 2/27/2008
carol: 2/21/2008
wwang: 1/7/2008
ckniffin: 12/18/2007
ckniffin: 11/11/2003
carol: 11/11/2003
ckniffin: 11/11/2003
ckniffin: 11/10/2003
joanna: 11/8/2003
ckniffin: 11/7/2003
joanna: 1/9/2001
carol: 1/9/2001