Investigating Novel Genetic Variants that Confer Susceptibility to Pesticide-induced Parkinson's Disease

J. David Gladstone Institutes, San Francisco CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Exposure to various pesticides has been established as an environmental factor that increases risk of Parkinson’s disease (PD). The biological impact of environmental risks is largely dependent on genetically- determined factors, but identifying these genetic factors through purely epidemiological studies is complicated both by genetic heterogeneity and uncertainties about lifelong pesticide exposure levels. This proposal aims to provide biological validation of novel candidate gene variants associated with increased susceptibility to pesticide-induced PD. We have identified candidate gene variants based on analysis of the FAME study database, which includes detailed clinical and pesticide exposure data from 493 agricultural workers of whom 100 developed PD. The novel gene candidates were identified using whole genome sequencing and gene burden analysis stratified across all of the pesticide exposure groups as well as for each individual group (paraquat, rotenone, permethrine, dieldrin). In this proposal we aim to biologically validate the importance of these variants using two complementary systems: iPSC-derived human dopaminergic neuronal cultures and a mouse model of paraquat-induced Parkinsonism. Candidate genes will be down-regulated in the human neuronal cultures using a CRISPRi approach and upregulated using lentiviral vectors to determine effects of gene expression on pesticide-induced cell death, oxidative stress, DNA damage, and mitochondrial morphological alterations. In parallel, genes of interest will be down-regulated or up-regulated in mouse substantia nigra using viral vectors in order to determine if dopaminergic susceptibility specifically to paraquat is influenced by these genes in the intact sustantia nigra of live animals. Success in these studies will both identify novel genetic variants and gene targets that influence dopaminergic susceptibility to pesticide toxicants and establish a platform for evaluating of other candidate gene variants and toxicants.