Abstract
Over the last decades, increasing knowledge about the genetic architecture of Parkinson’s disease has provided novel insights into the pathogenesis of the disorder, generating hypotheses for further research. Characterizing the role of SNCA, encoding the α-synuclein protein, has been a particularly important aspect of this development. The identification of SNCA as the first gene implicated in monogenic parkinsonism led to the recognition of α-synuclein as a key protein in the pathogenesis and a major component of pathological hallmark lesions. An association between common variants in SNCA and risk of sporadic Parkinson’s disease has been established through numerous studies. We review our current understanding of SNCA variability contributing to Parkinson’s disease, highlighting the characterization of functionally relevant susceptibility alleles as a major future challenge. We argue that new strategies will be needed to pinpoint the variants that are ultimately responsible for the signals detected in association studies, where targeted resequencing may represent an attractive initial approach.
Similar content being viewed by others
References
Duvoisin RC (1986) Etiology of Parkinson's disease: current concepts. Clin Neuropharmacol 9(Suppl 1):S3–S21
Hardy J (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68(2):201–206
Bekris LM, Mata IF, Zabetian CP (2010) The genetics of Parkinson disease. J Geriatr Psychiatry Neurol 23(4):228–242
Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8(8):2804–2815
Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 90(23):11282–11286
Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345(1):27–32
Xia Y, Saitoh T, Ueda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (2001) Characterization of the human alpha-synuclein gene: genomic structure, transcription start site, promoter region and polymorphisms. J Alzheimers Dis 3(5):485–494
Vekrellis K, Rideout HJ, Stefanis L (2004) Neurobiology of alpha-synuclein. Mol Neurobiol 30(1):1–21
Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329(5999):1663–1667
Bayer TA, Jakala P, Hartmann T, Havas L, McLean C, Culvenor JG, Li QX, Masters CL, Falkai P, Beyreuther K (1999) Alpha-synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease beta-amyloid plaque cores. Neurosci Lett 266(3):213–216
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388(6645):839–840
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276(5321):2045–2047
Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24(2):197–211
Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 14(5):504–506
Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 14(5):501–503
Angot E, Steiner JA, Hansen C, Li JY, Brundin P (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9(11):1128–1138
Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2(7):492–501
Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6):S2–S12
Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC (1990) A large kindred with autosomal dominant Parkinson's disease. Ann Neurol 27(3):276–282
Muenter MD, Forno LS, Hornykiewicz O, Kish SJ, Maraganore DM, Caselli RJ, Okazaki H, Howard FM Jr, Snow BJ, Calne DB (1998) Hereditary form of parkinsonism—dementia. Ann Neurol 43(6):768–781
Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC (1996) Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 274(5290):1197–1199
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18(2):106–108
Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55(2):164–173
Spellman GG (1962) Report of familial cases of parkinsonism. Evidence of a dominant trait in a patient's family. JAMA 179:372–374
Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, Hardy J, Dickson DW (2000) Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 99(6):663–672
Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M, Maraganore D, Gwinn-Hardy K, Wszolek Z, Dickson D, Langston JW (2004) Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55(2):174–179
Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) Alpha-synuclein locus triplication causes Parkinson's disease. Science 302(5646):841
Chartier-Harlin MC, 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 (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364(9440):1167–1169
Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 364(9440):1169–1171
Ross OA, Braithwaite AT, Skipper LM, Kachergus J, Hulihan MM, Middleton FA, Nishioka K, Fuchs J, Gasser T, Maraganore DM, Adler CH, Larvor L, Chartier-Harlin MC, Nilsson C, Langston JW, Gwinn K, Hattori N, Farrer MJ (2008) Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann Neurol 63(6):743–750
Farrer MJ (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7(4):306–318
Ibanez P, Lesage S, Janin S, Lohmann E, Durif F, Destee A, Bonnet AM, Brefel-Courbon C, Heath S, Zelenika D, Agid Y, Durr A, Brice A (2009) Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Arch Neurol 66(1):102–108
Lill CM, Roehr JT, McQueen MB, Kavvoura F, Bagade S, Schjeide BMM, Schjeide L, Meissner E, Zauft U, Allen NC, Tanzi R, Khoury MJ, Ioannidis JPA, Bertram L. The PDGene database. Alzheimer Research Forum. http://www.pdgene.org/. Accessed 11 May 2011
Xia Y, Rohan de Silva HA, Rosi BL, Yamaoka LH, Rimmler JB, Pericak-Vance MA, Roses AD, Chen X, Masliah E, DeTeresa R, Iwai A, Sundsmo M, Thomas RG, Hofstetter CR, Gregory E, Hansen LA, Katzman R, Thal LJ, Saitoh T (1996) Genetic studies in Alzheimer's disease with an NACP/alpha-synuclein polymorphism. Ann Neurol 40(2):207–215
Kruger R, Vieira-Saecker AM, Kuhn W, Berg D, Muller T, Kuhnl N, Fuchs GA, Storch A, Hungs M, Woitalla D, Przuntek H, Epplen JT, Schols L, Riess O (1999) Increased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann Neurol 45(5):611–617
Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, Ashizawa T (2000) Polymorphism of NACP-Rep1 in Parkinson's disease: an etiologic link with essential tremor? Neurology 54(5):1195–1198
Farrer M, Maraganore DM, Lockhart P, Singleton A, Lesnick TG, de Andrade M, West A, de Silva R, Hardy J, Hernandez D (2001) Alpha-synuclein gene haplotypes are associated with Parkinson's disease. Hum Mol Genet 10(17):1847–1851
Tan EK, Tan C, Shen H, Chai A, Lum SY, Teoh ML, Yih Y, Wong MC, Zhao Y (2003) Alpha synuclein promoter and risk of Parkinson's disease: microsatellite and allelic size variability. Neurosci Lett 336(1):70–72
Mellick GD, Maraganore DM, Silburn PA (2005) Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease. Neurosci Lett 375(2):112–116
Parsian A, Racette B, Zhang ZH, Chakraverty S, Rundle M, Goate A, Perlmutter JS (1998) Mutation, sequence analysis, and association studies of alpha-synuclein in Parkinson's disease. Neurology 51(6):1757–1759
Khan N, Graham E, Dixon P, Morris C, Mander A, Clayton D, Vaughan J, Quinn N, Lees A, Daniel S, Wood N, de Silva R (2001) Parkinson's disease is not associated with the combined alpha-synuclein/apolipoprotein E susceptibility genotype. Ann Neurol 49(5):665–668
Spadafora P, Annesi G, Pasqua AA, Serra P, Ciro Candiano IC, Carrideo S, Tarantino P, Civitelli D, De Marco EV, Nicoletti G, Annesi F, Quattrone A (2003) NACP-REP1 polymorphism is not involved in Parkinson's disease: a case–control study in a population sample from southern Italy. Neurosci Lett 351(2):75–78
Mizuta I, Nishimura M, Mizuta E, Yamasaki S, Ohta M, Kuno S (2002) Meta-analysis of alpha synuclein/NACP polymorphism in Parkinson's disease in Japan. J Neurol Neurosurg Psychiatry 73(3):350
Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296(6):661–670
Kay DM, Factor SA, Samii A, Higgins DS, Griffith A, Roberts JW, Leis BC, Nutt JG, Montimurro JS, Keefe RG, Atkins AJ, Yearout D, Zabetian CP, Payami H (2008) Genetic association between alpha-synuclein and idiopathic Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet 147B(7):1222–1230
Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, Pant PV, Frazer KA, Cox DR, Ballinger DG (2005) High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 77(5):685–693
Izumi Y, Morino H, Oda M, Maruyama H, Udaka F, Kameyama M, Nakamura S, Kawakami H (2001) Genetic studies in Parkinson's disease with an alpha-synuclein/NACP gene polymorphism in Japan. Neurosci Lett 300(2):125–127
Mizuta I, Satake W, Nakabayashi Y, Ito C, Suzuki S, Momose Y, Nagai Y, Oka A, Inoko H, Fukae J, Saito Y, Sawabe M, Murayama S, Yamamoto M, Hattori N, Murata M, Toda T (2006) Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum Mol Genet 15(7):1151–1158
Tan EK, Chai A, Teo YY, Zhao Y, Tan C, Shen H, Chandran VR, Teoh ML, Yih Y, Pavanni R, Wong MC, Puvan K, Lo YL, Yap E (2004) Alpha-synuclein haplotypes implicated in risk of Parkinson's disease. Neurology 62(1):128–131
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 MJ (2004) Alpha-synuclein promoter confers susceptibility to Parkinson's disease. Ann Neurol 56(4):591–595
Mueller JC, Fuchs J, Hofer A, Zimprich A, Lichtner P, Illig T, Berg D, Wullner U, Meitinger T, Gasser T (2005) Multiple regions of alpha-synuclein are associated with Parkinson's disease. Ann Neurol 57(4):535–541
Winkler S, Hagenah J, Lincoln S, Heckman M, Haugarvoll K, Lohmann-Hedrich K, Kostic V, Farrer M, Klein C (2007) Alpha-synuclein and Parkinson disease susceptibility. Neurology 69(18):1745–1750
Myhre R, Toft M, Kachergus J, Hulihan MM, Aasly JO, Klungland H, Farrer MJ (2008) Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population. Acta Neurol Scand 118(5):320–327
Pankratz N, Nichols WC, Elsaesser VE, Pauciulo MW, Marek DK, Halter CA, Wojcieszek J, Rudolph A, Pfeiffer RF, Foroud T (2009) Alpha-synuclein and familial Parkinson's disease. Mov Disord 24(8):1125–1131
Rajput A, Vilarino-Guell C, Rajput ML, Ross OA, Soto-Ortolaza AI, Lincoln SJ, Cobb SA, Heckman MG, Farrer MJ, Rajput A (2009) Alpha-synuclein polymorphisms are associated with Parkinson's disease in a Saskatchewan population. Mov Disord 24(16):2411–2414
Mata IF, Shi M, Agarwal P, Chung KA, Edwards KL, Factor SA, Galasko DR, Ginghina C, Griffith A, Higgins DS, Kay DM, Kim H, Leverenz JB, Quinn JF, Roberts JW, Samii A, Snapinn KW, Tsuang DW, Yearout D, Zhang J, Payami H, Zabetian CP (2010) SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol 67(11):1350–1356
Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, Aasly J, Annesi G, Bozi M, Brighina L, Chartier-Harlin MC, Destee A, Ferrarese C, Ferraris A, Gibson JM, Gispert S, Hadjigeorgiou GM, Jasinska-Myga B, Klein C, Kruger R, Lambert JC, Lohmann K, van de Loo S, Loriot MA, Lynch T, Mellick GD, Mutez E, Nilsson C, Opala G, Puschmann A, Quattrone A, Sharma M, Silburn PA, Stefanis L, Uitti RJ, Valente EM, Vilarino-Guell C, Wirdefeldt K, Wszolek ZK, Xiromerisiou G, Maraganore DM, Farrer MJ (2011) Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 69(5):778–792
Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Kruger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 41(12):1308–1312
Ross OA, Gosal D, Stone JT, Lincoln SJ, Heckman MG, Irvine GB, Johnston JA, Gibson JM, Farrer MJ, Lynch T (2007) Familial genes in sporadic disease: common variants of alpha-synuclein gene associate with Parkinson's disease. Mech Ageing Dev 128(5–6):378–382
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753
Singleton AB, Hardy J, Traynor BJ, Houlden H (2011) Towards a complete resolution of the genetic architecture of disease. Trends Genet 26(10):438–442
Spencer CC, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G, Barker RA, Bellenguez C, Bhatia K, Blackburn H, Blackwell JM, Bramon E, Brown MA, Brown MA, Burn D, Casas JP, Chinnery PF, Clarke CE, Corvin A, Craddock N, Deloukas P, Edkins S, Evans J, Freeman C, Gray E, Hardy J, Hudson G, Hunt S, Jankowski J, Langford C, Lees AJ, Markus HS, Mathew CG, McCarthy MI, Morrison KE, Palmer CN, Pearson JP, Peltonen L, Pirinen M, Plomin R, Potter S, Rautanen A, Sawcer SJ, Su Z, Trembath RC, Viswanathan AC, Williams NW, Morris HR, Donnelly P, Wood NW (2011) Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet 20(2):345–353
Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A (2006) Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5(11):911–916
Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 41(12):1303–1307
Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simon-Sanchez J, Schulte C, Lesage S, Sveinbjornsdottir S, Stefansson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW (2011) Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377(9766):641–649
Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW, Doheny KF, Gusella JF, Nichols WC, Foroud T, Myers RH (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 124(6):593–605
Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Zuchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance M, Haines J, Vance JM, Martin ER (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74(2):97–109
Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 42(9):781–785
Saad M, Lesage S, Saint-Pierre A, Corvol JC, Zelenika D, Lambert JC, Vidailhet M, Mellick GD, Lohmann E, Durif F, Pollak P, Damier P, Tison F, Silburn PA, Tzourio C, Forlani S, Loriot MA, Giroud M, Helmer C, Portet F, Amouyel P, Lathrop M, Elbaz A, Durr A, Martinez M, Brice A (2011) Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population. Hum Mol Genet 20(3):615–627
Simon-Sanchez J, van Hilten JJ, van de Warrenburg B, Post B, Berendse HW, Arepalli S, Hernandez DG, de Bie RM, Velseboer D, Scheffer H, Bloem B, van Dijk KD, Rivadeneira F, Hofman A, Uitterlinden AG, Rizzu P, Bochdanovits Z, Singleton AB, Heutink P (2011) Genome-wide association study confirms extant PD risk loci among the Dutch. Eur J Hum Genet 19(6):655–661
Hadjigeorgiou GM, Xiromerisiou G, Gourbali V, Aggelakis K, Scarmeas N, Papadimitriou A, Singleton A (2006) Association of alpha-synuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset. Mov Disord 21(4):534–539
Mata IF, 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 KW, Edwards KL, Zabetian CP (2011) Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease. Mov Disord 26(5):819–823
Phillips PC (2008) Epistasis—the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 9(11):855–867
Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, Ban M, Spillantini MG, Compston A, Burn DJ, Chinnery PF, Barker RA, Sawcer SJ (2007) Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 62(2):145–153
Mamah CE, Lesnick TG, Lincoln SJ, Strain KJ, de Andrade M, Bower JH, Ahlskog JE, Rocca WA, Farrer MJ, Maraganore DM (2005) Interaction of alpha-synuclein and tau genotypes in Parkinson's disease. Ann Neurol 57(3):439–443
Wider C, Vilarino-Guell C, Heckman MG, Jasinska-Myga B, Ortolaza-Soto AI, Diehl NN, Crook JE, Cobb SA, Bacon JA, Aasly JO, Gibson JM, Lynch T, Uitti RJ, Wszolek ZK, Farrer MJ, Ross OA (2011) SNCA, MAPT, and GSK3B in Parkinson disease: a gene–gene interaction study. Eur J Neurol 18(6):876–881
Botta-Orfila T, Ezquerra M, Rios J, Fernandez-Santiago R, Cervantes S, Samaranch L, Pastor P, Marti MJ, Munoz E, Valldeoriola F, Aguilar M, Calopa M, Hernandez-Vara J, Tolosa E (2010) Lack of interaction of SNCA and MAPT genotypes in Parkinson's disease. Eur J Neurol 18(3):e32
Brighina L, Frigerio R, Schneider NK, Lesnick TG, de Andrade M, Cunningham JM, Farrer MJ, Lincoln SJ, Checkoway H, Rocca WA, Maraganore DM (2008) Alpha-synuclein, pesticides, and Parkinson disease: a case–control study. Neurology 70(16 Pt 2):1461–1469
McCulloch CC, Kay DM, Factor SA, Samii A, Nutt JG, Higgins DS, Griffith A, Roberts JW, Leis BC, Montimurro JS, Zabetian CP, Payami H (2008) Exploring gene–environment interactions in Parkinson's disease. Hum Genet 123(3):257–265
Gatto NM, Rhodes SL, Manthripragada AD, Bronstein J, Cockburn M, Farrer M, Ritz B (2010) Alpha-synuclein gene may interact with environmental factors in increasing risk of Parkinson's disease. Neuroepidemiology 35(3):191–195
Fuchs J, Tichopad A, Golub Y, Munz M, Schweitzer KJ, Wolf B, Berg D, Mueller JC, Gasser T (2008) Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain. FASEB J 22(5):1327–1334
Volles MJ, Lansbury PT Jr (2003) Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 42(26):7871–7878
Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH, Riek R (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 108(10):4194–4199
Markopoulou K, Wszolek ZK, Pfeiffer RF, Chase BA (1999) Reduced expression of the G209A alpha-synuclein allele in familial Parkinsonism. Ann Neurol 46(3):374–381
Kobayashi H, Kruger R, Markopoulou K, Wszolek Z, Chase B, Taka H, Mineki R, Murayama K, Riess O, Mizuno Y, Hattori N (2003) Haploinsufficiency at the alpha-synuclein gene underlies phenotypic severity in familial Parkinson's disease. Brain 126(Pt 1):32–42
Voutsinas GE, Stavrou EF, Karousos G, Dasoula A, Papachatzopoulou A, Syrrou M, Verkerk AJ, van der Spek P, Patrinos GP, Stoger R, Athanassiadou A (2010) Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease. Hum Mutat 31(6):685–691
Chiba-Falek O, Nussbaum RL (2001) 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 Mol Genet 10(26):3101–3109
Cronin KD, Ge D, Manninger P, Linnertz C, Rossoshek A, Orrison BM, Bernard DJ, El-Agnaf OM, Schlossmacher MG, Nussbaum RL, Chiba-Falek O (2009) Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain. Hum Mol Genet 18(17):3274–3285
Scherzer CR, Grass JA, Liao Z, Pepivani I, Zheng B, Eklund AC, Ney PA, Ng J, McGoldrick M, Mollenhauer B, Bresnick EH, Schlossmacher MG (2008) GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein. Proc Natl Acad Sci U S A 105(31):10907–10912
Jowaed A, Schmitt I, Kaut O, Wullner U (2010) Methylation regulates alpha-synuclein expression and is decreased in Parkinson's disease patients' brains. J Neurosci 30(18):6355–6359
Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A (2010) CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson's disease. PLoS One 5(11):e15522
Beyer K (2006) Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 112(3):237–251
McCarthy JJ, Linnertz C, Saucier L, Burke JR, Hulette CM, Welsh-Bohmer KA, Chiba-Falek O (2010) The effect of SNCA 3′ region on the levels of SNCA-112 splicing variant. Neurogenetics 12(1):59–64
Wikimedia Commons. http://commons.wikimedia.org/wiki/File:Lewy_Body_alphaSynuclein.jpg. Accessed 11 May 2011
International HapMap Consortium (2003) The International HapMap Project. Nature 426(6968):789–796
International HapMap Project. http://hapmap.ncbi.nlm.nih.gov. Accessed 11 May 2011
Acknowledgments
The authors are supported by grants from the South-Eastern Norway Regional Health Authority and the Research Council of Norway.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pihlstrøm, L., Toft, M. Genetic variability in SNCA and Parkinson’s disease. Neurogenetics 12, 283–293 (2011). https://doi.org/10.1007/s10048-011-0292-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-011-0292-7