α-Synuclein Promoter Variability Affects Risk for Parkinson's Disease

Abstract & Commentary

By Claire Henchcliffe, MD, DPhil, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.

Synopsis: α-synuclein mutations leading to Parkinson's disease are extremely rare. However, based upon this study, variability in the gene promoter may account for up to 3% of the risk of Parkinson's disease in the general population.

Source: Maraganore DM, et al. Collaborative Analysis of Alpha-Synuclein Gene Promoter Variability and Parkinson Disease. JAMA. 2006;296:661-670.

This study was conducted by the genetic epidemiology of Parkinson's Disease Consortium, which includes 3 cores (coordinating, statistical, and laboratory) and 18 global sites. Maraganore and colleagues performed allele-length variability analysis of the 3 most common dinucleotide repeat sequence (REP1) alleles (263 base-pairs [bp], 261 bp and 259 bp) of the α-synuclein (SNCA) gene promoter, and of the -770 and -116 bp single-nucleotide polymorphism (SNP) genotypes in Parkinson's disease (PD) patients and controls. The 11 participating sites were chosen on the basis of 1) intent to collaborate and to provide DNA samples for analysis by the consortium laboratory core or 2) provision of existing data determined to have a low genotyping error rate (as judged by re-analysis by the consortium laboratory core of > 20 samples per site, with inter-laboratory reliability > 90%, and required concordance with the Hardy-Weinberg equilibrium). The final analysis comprised 2692 cases and 2652 controls. Genotypes defined by the 263 bp REP1 allele were associated with an increased risk for PD (OR 1.43; 95% confidence interval [CI], 1.22-1.69). Genotypes defined by the 259 bp allele were associated with a decreased risk (OR 0.86, 95% CI, 0.79-0.94) for PD. However, REP1 genotypes were not associated with age of onset or gender. The frequency of haplotypes defined by the REP1, -770, and -116 loci was significantly different in cases compared to controls (P < 0.001).

Commentary

SNCA gene mutations were among the first to be linked to autosomal dominant familial PD.1 Currently, there are 3 known SNCA mutations associated with PD: SNCA 209G>A (Ala53Thr), SNCA 88G>C (Ala30Pro), and SNCA 188G>A (Glu46Lys). In addition, SNCA multiplication leads to familial PD (PARK4), suggesting α-synuclein over-expression as a possible mechanism leading to neurodegeneration. α-synuclein is expressed throughout the brain and is found in Lewy bodies, the characteristic cytoplasmic inclusions found in dopaminergic neurons in PD. Until now, the SNCA mutations described have been extremely rare and considered of doubtful, practical significance for PD patients seen in office practice. In the present study, Maraganore et al have extended the potential significance of the SNCA gene in PD beyond monogenetic Mendelian inheritance. Their findings suggest that the 263 bp SNCA REP1 allele is a susceptibility gene for PD in a large cohort of familial and sporadic PD cases worldwide. This will clearly stimulate further investigation to confirm and better define the level of attributable risk and to further investigate association with specific disease characteristics, such as age of onset. Maraganore et al estimate that SNCA REP1 locus variability may explain approximately 3% of the risk for PD in the general population, pointing to significant clinical implications. If correct, interventions targeting SNCA expression might be useful for primary prevention of PD. SNCA, therefore, joins other proposed PD susceptibility genes, such as the tau H1 haplotype, variations in gene sequences of monoamine oxidase B, and glucocerebrosidase (better known for its role in Gaucher's disease), among others. Moreover, despite problems associated with this study design, Maraganore et al have established an important paradigm for research in genetics of complex disorders like PD, and have demonstrated the value of a worldwide collaborative effort, providing large numbers of clinically and genetically characterized subjects.

Reference

1. Farrer MJ. Genetics of Parkinson's Disease: Paradigm Shifts and Future Prospects. Nat Rev Genet. 2006;7:306-318.