Genome-wide analysis reveals genes mediating resistance to paraquat neurodegeneration in Drosophila
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Parkinson’s 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 person’s 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 SUMMARY
Paraquat 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.
