Investigating environmental and gene-environment contributors to Parkinson's disease risk by coupling quantitative environmental exposure data to iPSC modeling

PROJECT SUMMARY Parkinson's Disease (PD) is considered a “man-made” pandemic, triggered in part by industrialization that has entailed increased production needs and exposure to toxicants resulting from that growth. Despite the discovery of important genetic risk factors, a substantial amount of etiologic risk for idiopathic PD is environmental, with pesticide exposure being a clear and documented risk factor. As a result, understanding the interaction between genetic drivers and environmental risk factors has significant potential to inform etiology and treatment of PD. This project will investigate how environmental factors, specifically pesticides, influence the development of PD at the level of effects on midbrain dopaminergic (mDA) neurons, a cell type whose loss is the hallmark of PD pathology. The work is informed by a paradigm in which highly quantitative pesticide exposure data from a large PD cohort in California is linked to a screening platform using patient stem cell (iPSC)-derived mDA neurons. Fifty-three pesticides were linked to PD with this method and ten proved directly toxic to mDA neurons. The proposed work will: (1) deeply dissect mechanisms of mDA neuron toxicity for top hits with a focus on mitochondrial and cytoskeletal consequences of trifluralin exposure; (2) explore the role of glia in modulating toxicity using a triculture approach to ask how other PD-associated pesticides alter astrocyte and microglial biology to influence mDA neuron pathology; and (3) use population-level modeling of sporadic PD in a dish to build a platform that will stratify cells from ~100 donors functionally based on responses to pesticides and then use computational methods to reconstruct which cell lines are disproportionately affected. This will identify shared phenotypes among genetically disparate samples. The career development plan is designed to support the candidate's goal of becoming an independent investigator at an academic medical center, treating PD patients in clinic while concurrently leading a research team studying their disease. A strong mentorship and collaborative team in a vibrant research environment is led by a supportive neurology chairperson (Batchelor), outstanding physician scientists with expertise spanning from neurodegeneration (Khurana, Selkoe) to public health and epidemiology (Ritz) to translational neuroscience (Rubin, Studer, Powell). This mentorship team, along with extensive research training and relevant coursework, will position the candidate for success. The institutional resources available through Brigham and Women's Hospital, and Harvard University will support the candidate's career in an environment that makes high impact contributions and collaborative endeavors achievable. The successful execution of this proposal will position the candidate along a path for an independent career as a physician scientist studying the interplay of gene-environment interactions in PD to better treat and prevent this disease.