SNCA Variant Associated With Parkinson Disease and Plasma α-Synuclein Level
Open Access
- 1 November 2010
- journal article
- research article
- Published by American Medical Association (AMA) in Archives of Neurology
- Vol. 67 (11), 1350-1356
- https://doi.org/10.1001/archneurol.2010.279
Abstract
The SNCA gene encodes α-synuclein, a small (140 amino acid) protein localized, in part, to presynaptic terminals that modulates vesicle trafficking and neurotransmitter release.1,2 A link between α-synuclein and Parkinson disease (PD) was first demonstrated in 1997 when a missense mutation (A53T) in SNCA was reported to cause autosomal dominant parkinsonism in a large Italian family (the Contursi kindred).3 Shortly thereafter, α-synuclein was shown to be a major component of Lewy bodies, the pathologic hallmark of both familial and sporadic PD.4 Triplication of the gene was later discovered to cause dominant early-onset PD, indicating that overexpression of wild-type synuclein was sufficient to cause disease.5,6 However, missense mutations and multiplications of SNCA proved to be rare, which raised the question of whether common variants with more subtle functional effects might modify susceptibility for PD. Our group and others have reported an association between PD and REP1 (D4S3481), a complex repeat polymorphism located approximately 10 kilobases (kb) upstream from the SNCA translation start site.7-9REP1 is essentially triallelic, and compared with the intermediate-length allele (“261”), the longest allele (“263”) is associated with increased risk and the shortest allele (“259”) with decreased risk for PD. In vitro data suggest that, rather than simply serving as a genetic marker, REP1 alleles might differentially regulate SNCA transcription, possibly through interactions with the DNA-binding protein PARP-1.10,11 Association analyses of SNCA single-nucleotide polymorphisms (SNPs), including 2 small genome-wide association studies (GWASs), yielded mixed results over the past decade.9,12-14 However, 3 larger GWASs15-17 published in 2009 all reported strong association signals from SNPs within SNCA.This publication has 30 references indexed in Scilit:
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