Comparative proteomic analysis of environmental and genetic models of Parkinson’s disease highlights the role of purine metabolism

Abstract

Parkinson’s Disease (PD) is the second most common neurodegenerative disease, with many cases attributed to environmental exposures. Paraquat (PQ), is a pesticide and neurotoxicant strongly associated with increased PD risk. PQ is a weak inhibitor of complex I of the electron transport chain, and while its acute toxicity is well understood, the mechanism by which PQ exposure contributes to PD pathophysiology remains unclear. Additionally, the mechanism of PQ neurotoxicity has not been effectively related to genetic forms of PD. Given that PD is a heterogeneous disease with genetic and environmental determinants, we systematically compared proteomic changes that occur in genetic and environmental models of PD. Herein, we leveraged untargeted omics approaches to differentiate between peripheral and CNS-specific changes in the proteome. We performed a comparative proteomic analysis on the heads and bodies of Drosophila models of PQ ingestion and neuronal α-synuclein expression. Additionally, we validated the findings with metabolomic analysis of brainstems from a murine PQ inhalation model. Our findings indicate shared dysregulated pathways across all models, highlighting similar mechanisms. Specifically, we identified a glia-specific role in purine nucleotide metabolism upstream of inosine catabolism, which may protect against PQ neurotoxicity. This work identifies potential biomarkers and targets for drug intervention.