Rationale & Objective
The cause of >90% of Parkinson's disease (PD) is unknown. Twin studies suggest that a substantial proportion of disease is due to environmental factors, yet few specific environmental risk factors have been consistently associated with PD risk. We and others hypothesize that environmental associations are obscured by genetic variations that confer differential susceptibility, so-called gene-environment interaction. However, to date, only a handful of significant gene-environment interactions have been reported, few have been replicated, and virtually none have been explored for functional significance using experimental models.
We will meet these challenges by (1) using whole genome sequencing (WGS) and bioinformatic approaches to predict which genes and variants are likely to be functionally significant modifiers of PD susceptibility in well-characterized subjects with pesticide and other persistent organic pollutant exposures characterized both historically and through serum measurements and (2) experimentally testing the most promising of these predictions for functional significance using iPSC-derived neuronal cell lines.
The ultimate goal of this work is to implement a "personalized toxicology" to reduce risk to Service members and the general population by integrating environmental, genomic, and functional data to characterize individual risk for PD.
This project has 3 major aims. (1) We will validate the effect of loss of function of the gene encoding glutathione-S-transferase T1 (GSTT1) on susceptibility of dopaminergic neurons to the herbicide paraquat and several other common toxicants. In our prior studies we found that, in persons devoid of GSTT1 (which occurs in 20% of the population), exposure to the commonly used herbicide paraquat was associated with an 11-fold increased risk of PD. We will validate this epidemiologic observation by exposing neurons derived from induced pluripotent stem cells (iPSC) lacking GSTT1 to paraquat, 2,4-D, permethrin, and trichloroethylene. (2) We will use whole genome sequencing to identify genes that are likely to increase susceptibility to a wide range of specific environmental toxicants in a highly-exposed population of professional pesticide applicators. (3) Using iPSC-derived neurons engineered to have these specific genetic deficits, we will confirm and identify mechanisms underlying these newly identified gene-toxicant interactions
This project will directly address Impact Award Focus Area: Genetic stratification of suspected environment factors that are quantifiable on the risk of developing Parkinson's disease.
Applicability of Research
What types of patients will it help and how will it help them? This work is highly relevant to all populations. It is especially relevant to former, current, and future military personnel, because we will focus on toxicants that they are likely to be exposed to. This work will lay a foundation for the implementation of precision toxicology, targeting the specific molecular mechanisms causing disease in exposed individuals.
What are the potential clinical applications, benefits, and risks? Currently, we cannot prevent PD. Although researchers suspect that environmental factors are important, few environmental factors have been conclusively linked, suggesting that only certain people are susceptible to specific risk factors. If we can identify and validate gene-environment interactions, we may be able to implement individual preventive measures to help prevent people from getting PD.
What is the projected time it may take to achieve a patient-related outcome? Our study will last 3 years. We expect to publish our findings at project completion.
What is the likely impact of this study on slowing the progression of, preventing, and/or curing PD? Learning how genes and environment combine to cause PD will allow us to implement preventive strategies. These can be both public health strategies to reduce levels of specific compounds in the environment, as well as individualized prevention strategies to limit specific exposures in genetically susceptible persons.