Understanding the Role of Gene-Environment Interactions in the Degeneration of Human Dopaminergic Neurons in Parkinson's Disease
Abstract
Gene environment interactions (GxE) are key to better understanding Parkinsons disease (PD) and identifying risk factorsfor intervention. For this grant, we identified in an untargeted manner a number of specific pesticides that increased PD riskand then tested their effects in the dish in the context of mutations in the alpha-synuclein gene. Our results in humanswere based on the PEG cohort and leveraged agricultural pesticide application records in California to established longterm exposure profiles for over 250 widely used agricultural pesticides for 1,870 PD patients and population-based controls.Using this data, we generated a list of 33 pesticide toxicants that are both significantly associated with PD (FDR<0.01) andhave exposure in -syn SNPs variant carriers. In-vitro experiments showed that a key genetic risk factor (alpha-synuclein)in PD created sensitivities to a number of toxicants that we had identified as increasing risk of PD in humans suggestingthat there may be gene-toxicant interactions at the level of the dopamine neurons in patients. Specifically, in synergy withthe lab-based teams (Rubin and Khurana), h-IPSc derived from patients with PD caused by synuclein mutations weobserved effects for PD-linked pesticides with respect to survival, neurite outgrowth and calcium signaling. We then furtherinvestigated hits from these lab-based screens in conjunction with SNCA and GBA genetic data to assess GxE interactionswith pathway relevant SNPs in the PEG study.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2023
- Accession Number
- AD1201619
Entities
People
- Beate Ritz
Organizations
- University of California, Los Angeles