Genome-wide analysis reveals genes mediating resistance to paraquat neurodegeneration in Drosophila

Abstract

Parkinsons disease (PD) is thought to develop through a complex interplay of genetic and environmental factors. Epidemiological studies have linked exposure to certain pesticides such as paraquat with elevated PD risk, although how a persons genetic makeup influences disease risk upon exposure remains unknown. Here, we used a genome-wide approach to uncover genes that play a role in resistance to paraquat-induced dopaminergic neurodegeneration in Drosophila. We developed a paraquat exposure model displaying delayed-onset dopaminergic (DA) neurodegeneration to recapitulate this aspect of human disease. We reveal that genetic background is a strong determinant of paraquat-induced DA neurodegeneration susceptibility across a series of nearly 200 fly strains called the Drosophila genetic reference panel (DGRP). Through unbiased genome-wide analysis and follow-up validation, we identify two candidate paraquat resistance genes, luna and CG32264. In gene-level studies, decreased expression of luna or CG32264 is associated with paraquat-induced DA neuron loss while overexpression of either gene prevents neurodegeneration in vivo. The mammalian ortholog of CG32264 is Phactr2, which has previously been linked to human idiopathic PD risk in several populations. Hence, our results reveal genes regulating paraquat-induced DA neuron loss that intersect with human PD risk variants, supporting the potential relevance of our findings to PD and underscoring a role for gene-environment interactions in pesticide-related DA neurodegeneration. ARTICLE SUMMARYParaquat is a widely used herbicide linked to increased PD risk and to dopaminergic neurodegeneration in animal studies. Gene-environment interactions likely influence whether an individual exposed to paraquat eventually manifests PD and presents a major opportunity to yield insight into PD genetics. We developed a paraquat-induced neurodegeneration model in Drosophila, applied this model to nearly 200 fly strains belonging to the Drosophila Genetic Reference Panel and used a genome-wide association approach to identify candidate modifier genes of paraquat-induced dopamine neuron loss which we subsequently validated through RNAi and overexpression functional testing. Through this approach, we reveal two novel paraquat resistance genes, luna and CG32264. Strikingly, the putative mammalian ortholog of CG32264 (Phactr2) was previously linked to human PD, supporting the potential relevance of our findings to human disease.