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

ABSTRACT: Cigarette smoking is associated with reduced risk of developing Parkinson’s 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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE35930 | GEO | 2012/09/05

SECONDARY ACCESSION(S): PRJNA152069

REPOSITORIES: GEO

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

Project description:Cigarette smoking is associated with reduced risk of developing Parkinson’s 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. Drosophila female heads were dissected after exposure to plain food, food with paraquat, food with nicotine, or food with both paraquat and nicotine, and genome-wide expression was quantified using Affymetrix microarrays. 20 heads were pooled per replicate, with each treatment in triplicate, and all flies were dissected at the same timepoint, after 10 days of pretreatment (with 0.1 mg/ml nicotine or no nicotine, depending on treatment group), and then a further 6 days of treatment with either 5 mM paraquat or no paraquat, continuing on the pretreatment dose of nicotine. One biological replicate in the paraquat-only group showed RNA degradation and was not included in the normalization or subsequent analyses.

2012-09-05 | E-GEOD-35930 | biostudies-arrayexpress

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