Genetic basis of maneb-induced dopaminergic neurodegeneration in Drosophila

Abstract

Parkinsons disease (PD) is a complex neurodegenerative disease driven by combined genetic and environmental factors. Human studies support increased PD risk following exposure to the pesticide maneb yet animal studies generally report subtle or no dopaminergic phenotypes unless maneb is combined with additional pesticides. Consequently, it is unclear whether exposure to maneb alone promotes dopamine (DA) neurodegeneration and if so, what the underlying mechanisms are. We hypothesized that gene-environment interactions are major determinants of maneb-mediated neurodegeneration and in support of this find that DA neuron viability is quantitatively divergent among 186 maneb-exposed genetically varying fly strains from the Drosophila Genetic Reference Panel (DGRP). Through genome-wide association analysis we identify several candidate genetic modifiers of maneb-induced DA neurodegeneration and further validate two candidate genes, fz2 and CG14186 which we find potentiate maneb-induced DA neurodegeneration when knocked-down. fz2 and the mammalian ortholog of CG14186 (TMEM237) are both thought to be necessary for intact Wnt pathway signaling in nervous system development and maintenance. Accordingly, we find that adult-specific perturbation of Wnt signaling is sufficient to promote maneb-induced DA neuron loss. Collectively, these results support a role for gene-environment interactions in PD etiology and reveal candidate mediators of maneb-related DA neurodegeneration in vivo. ARTICLE SUMMARYExposure to the pesticide maneb has been linked to increased PD risk although animal models of neurodegeneration have produced mixed results. We developed a Drosophila model for delayed onset dopamine neuron loss following maneb exposure and find that maneb-related neurodegeneration is quantitatively divergent across a large collection of Drosophila strains. We use a genome-wide association approach with follow-up validation to identify candidate modifier genes, uncovering roles for fz2 and CG14186. Both genes are implicated in Wnt signaling and we further show that deregulated Wnt signaling in adults promotes maneb-induced dopamine neuron loss. These studies support a role for gene-environment interactions in maneb neurotoxicity and yield insight into the underlying genes involved.