EXPLORING THE IMPACT OF LRRK2 GENETIC MUTATIONS ON CELLULAR SUSCEPTIBILITY TO PESTICIDES AS A RISK FACTOR FOR PARKINSON’S DISEASE

Parkinson’s Disease (PD) is the most common movement disorder worldwide, thought to be influenced by genetic-environmental interactions. Mutations in LRRK2 are associated with genetic PD. Exposure to pesticides, like rotenone and glyphosate, have been linked to PD risk. To test the hypothesis that G2019S-LRRK2 mutation increases cellular susceptibility to pesticide-induced degeneration, SH-SY5Y cells stably overexpressing wild-type (WT)-LRRK2 or G2019S-LRRK2 were treated with rotenone or glyphosate for 72 h, with or without 1h pre-treatment with the LRRK2 kinase inhibitor, MLi-2. There was higher basal LRRK2 kinase activity in G2019S-LRRK2 compared to WT-LRRK2 cells, reflected by increased pSer935-LRRK2 levels relative to total LRRK2 levels. MLi-2 pre-treatment reduced kinase activity in both genotypes. G2019S-LRRK2 exhibited lower neurite length than WT-LRRK2 cells, indicating that mutation alone induces morphological deficits. Rotenone and glyphosate caused dose-dependent reductions in neurite length in both genotypes, particularly G2019S-LRRK2 cells. Mli-2 treatment increased neurite length of G2019S-LRRK2, but not WT-LRRK2, cells. MLi-2 pre-treatment attenuated the effects of rotenone and glyphosate on neurite length, in both cell types. Lysosomal function was assessed by measuring LAMP2 levels. G2019S-LRRK2 had lower LAMP2 levels than WT-LRRK2 cells, which were restored following MLi-2 treatment. Mli-2 had no effect on LAMP2 levels in WT-LRRK2 cells. Glyphosate, but not rotenone, significantly reduced LAMP2 levels in both cell types, an effect that was reversed by Mli-2 pre-treatment. These findings demonstrate that the G2019S-LRRK2 mutation impairs neurite outgrowth and lysosomal function and enhances vulnerability to pesticide-induced neurotoxicity, and that these pathological effects are mitigated by LRRK2 kinase inhibition.