Understanding the Role of Gene-Environment Interactions in the Degeneration of Human Dopaminergic Neurons in Parkinson's Disease
[Technical Report, Annual Report]
CALIFORNIA UNIV REGENTS LOS ANGELES
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Gene environment interactions GxE are key to better understanding PD. We are testing pesticides for their effects in the dish, and in the context of mutations in the synuclein and GBA genes that are also being analyzed in Dr. Ritzs epidemiologic cohort. Our experiments will enable us to answer whether key genetic risk factors create sensitivities inpatients to particular toxicants and we will ascertain whether gene-toxicant interactions play out specifically at the level of the dopamine neuron. To date, we have generated a unique set of reagents from patients with PD caused by synuclein and GBA mutations and observed differential effects to PD-linked pesticides and toxicants with respect to survival, neurite outgrowth and calcium signaling. From the PEG cohort data and leveraging agricultural pesticide application records CAPUR database discussed below, 1974-2018, we have established long-term exposure profiles for over 200 widely used agricultural pesticides for 1,870 PD patients and population-based controls. Using this data for analysis, we have generated a list of 33 pesticide toxicants that are both significantly associated with PD FDR0.01 and have exposure in both alpha-syn SNPs and GBA variant carriers. This epidemiologic analysis agnostically highlighted, out of pesticides widely used agriculturally in California over the study period, the most significantly associated with PD. In synergy, the lab-based teams Rubin and Khurana will in the next phase of research test these epidemiologically derived pesticides in in vitro cell lines in the context of mutations in the synuclein and GBA mechanisms. Validated hits from these screens will then be used in conjunction with SNCA and GBA genetic data to assess GxE interactions with pathway relevant SNPs in the PEG study.
- Medicine and Medical Research