This work confirms the association between synuclein and Parkinson disease (PD), which has been reported many times and complements a recent and excellent paper from the Gasser group. As with all meta-analyses, however, one has to worry that publication bias has prevented the publication of negative studies. The synuclein association for sporadic PD resembles the tau association for sporadic tangle disorders and seems to reflect a general principle that genetic variability at the loci underlying autosomal dominant disease contribute to the risk of their sporadic counterparts (Singleton et al., 2004) through a mechanism which involves increased expression of the risk allele.

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This study builds upon existing genotyping and combines studies to provide a compelling confirmation of the well-reported association between allele length of the promoter polymorphism REP1 in α-synuclein (SNCA) and risk for Parkinson disease (1-5). These data, along with previous functional data (6) and the observation that triplication of the SNCA locus causes disease (7) are absolutely consistent with the idea that increased production of α-synuclein is a risk factor for Parkinson disease and other Lewy body disorders. While this is unlikely to be predictive of disease risk, it reaffirms the predicted role of expression of the deposited species in diseases of protein deposition (8), consistent with SNCA multiplication in PD and trisomy 21/APP duplication in Alzheimer disease (9).

References:
1. 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. Increased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann Neurol. 1999 May;45(5):611-7. Abstract

2. Tan EK, Tan C, Shen H, Chai A, Lum SY, Teoh ML, Yih Y, Wong MC, Zhao Y. Alpha synuclein promoter and risk of Parkinson's disease: microsatellite and allelic size variability. Neurosci Lett. 2003 Jan 9;336(1):70-2. Abstract

3. 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. Alpha-synuclein haplotypes implicated in risk of Parkinson's disease. Neurology. 2004 Jan 13;62(1):128-31. Abstract

4. Mellick GD, Maraganore DM, Silburn PA. Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease. Neurosci Lett. 2005 Feb 28;375(2):112-6. Abstract

5. Hadjigeorgiou GM, Xiromerisiou G, Gourbali V, Aggelakis K, Scarmeas N, Papadimitriou A, Singleton A. Association of alpha-synuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset. Mov Disord. 2006 Apr;21(4):534-9. Abstract

6. Chiba-Falek O, Touchman JW, Nussbaum RL. Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene. Hum Genet. 2003 Oct;113(5):426-31. Abstract

7. 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. alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003 Oct 31;302(5646):841. Abstract

8. Singleton A, Myers A, Hardy J. The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R123-6. Abstract

9. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. Abstract

View all comments by Andrew Singleton