α-Synuclein, pesticides, and Parkinson disease

Abstract

Aggregation and fibrillization of the alpha-synuclein protein (encoded by the SNCA gene) may represent key events in the pathogenesis of Parkinson disease (PD). Variability in the length of a dinucleotide repeat sequence (REP1) within the SNCA promoter confers susceptibility to sporadic PD. Pesticide exposures may also confer susceptibility to PD. Our objective was to test possible joint effects of SNCA REP1 genotypes and pesticide exposures on the risk of PD. This was a case-control study. Cases were recruited prospectively from the Department of Neurology of the Mayo Clinic, Rochester, MN, after June 1, 1996. The control subjects included unaffected siblings of cases and unrelated population control subjects. We assessed pesticide exposures by telephone interview and genotyped SNCA REP1. Odds ratios (ORs) and 95% CIs were determined using conditional logistic regression models. There were 833 case-control pairs. We observed an increased risk of PD with increasing SNCA REP1 bp length (OR, 1.18 for each score unit; 95% CI, 1.02-1.37; p = 0.03). Pesticide exposures were associated with PD in younger subjects only (lowest quartile of age at study, <or=59.8 years; OR, 1.80; 95% CI, 1.12-2.87; p = 0.01 for all pesticides; OR, 2.46; 95% CI, 1.34-4.52; p = 0.004 for herbicides). In multivariate analyses, both SNCA REP1 score and pesticide exposures were significantly associated with PD in younger subjects, but there were no pairwise interactions. Our findings suggest that SNCA REP1 genotype and herbicides have independent effects on risk of Parkinson disease, primarily in younger subjects.