Identification of Pesticides Associated with an Increased Risk of Parkinson's Disease using a Multi-Screen Approach

Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by aggregation and transmission of alpha-synuclein (α-syn) protein and loss of dopaminergic neurons. The etiology of PD is multifactorial involving both genetic and environmental factors. Pesticide exposure has been associated with PD, but it is still unclear which of the hundreds of chemically and structurally diverse pesticides confer this association. While there are numerous pesticides currently registered for use in the United States, in this study, we focused on 62 pesticides used in the California Central Valley. We used 2 cell-based screens and a recently developed pesticide-wide association study (PWAS) analysis to identify candidates that increase the risk of PD. One cell-based screen tested for pesticides that alter autophagy and the other tested for their effect on α-syn transmission. To establish biological plausibility, pesticides that were positive in all 3 screens were tested for dopaminergic neurotoxicity in an in vivo zebrafish (ZF) model. The autophagy screen resulted in a total of 22 hits for alterations to either autophagosomes (16 hits) and lysosomes (14 hits) out of the 62 pesticides tested. The α-syn transmission screen resulted in 29 hits, and the PWAS resulted in 34 hits. Six pesticides were positive in all 3 screens and four of these pesticides induced aminergic neuron loss in ZF larvae. The majority of the pesticides identified in our screens have not previously been implicated as risk factors for PD but should be considered in future studies.