Effect of paraquat and nicotine on gene expression in a Drosophila melanogaster Parkinson's disease model

Cigarette smoking is associated with reduced risk of developing Parkinsons disease (PD). To identify genes that interact with nicotine/smoking, we performed hypothesis-free genome-wide experiments in a paraquat-induced Drosophila model and in a case-control study of PD. We demonstrated that nicotine extends life-span in paraquat-treated Drosophila (P=4E-30). Brain tissue from flies treated with combinations of paraquat and nicotine revealed elevated expression of CG14691 with paraquat which was restored with nicotine co-treatment (P(interaction)=2E-11, P(FDR-adjusted)=4E-7). Independently, variants in the 5 region of SV2C, a human ortholog of CG14691, gave the strongest signal for interaction with smoking (P(interaction)=9E-8). The effect of smoking on PD risk varied six-fold by SV2C genotype (P(heterogeneity)=4E-10). Moreover, SV2C variants identified here were associated with SVC2 gene-expression in the HapMap data. Present results suggest synaptic vesicle protein SV2C plays a role in PD pathogenesis, and that the SV2C genotype may be useful for clinical trials of nicotine for treating PD.

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Hill-Burns EM, Singh N, Ganguly P, Hamza TH, Montimurro J, Kay DM, Yearout D, Sheehan P, Frodey K, McLear JA, Feany MB, Hanes SD, Wolfgang WJ, Zabetian CP, Factor SA, Payami H