Abstract
Parkinson's Disease (PD) is the second most common neurodegenerative disease, with many cases being attributed to environmental contaminant exposures. Paraquat (PQ), is a pesticide and environmental neurotoxicant that has been strongly associated with increased risk of PD. PQ is known to be a weak inhibitor of complex I of the electron transport chain, and while its acute toxicity is well understood, the underlying mechanism by which PQ exposure contributes to PD pathophysiology remains unclear. Additionally, the mechanism of PQ neurotoxicity has yet to be effectively compared and related to genetic forms of PD. Given that PD is a heterogeneous disease with both genetic and environmental determinants, we sought to systematically compare the proteomic changes that occur in different genetic and environmental models of PD. In this study, we leveraged untargeted omics approaches to differentiate between systemic, peripheral, and CNS-specific changes in the proteome. We did this by performing a comparative proteomic analysis on the heads and bodies of Drosophila models of PQ ingestion and neuronal α-synuclein expression in males. Additionally, we validated the findings with metabolomic analysis of male and female brain stems from a murine PQ inhalation model using C57BL/6J mice. Our findings indicate shared dysregulated pathways across all models, highlighting similar mechanisms of action. 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 early points for biomarker detection and potential targets for drug intervention. SIGNIFICANCE STATEMENT: Neurodegenerative diseases such as Parkinson's disease (PD) pose a growing public health burden, yet disease-modifying therapies remain limited due to lack of mechanistic understanding and disease heterogeneity. Both genetic and environmental factors contribute to PD, complicating the identification of shared therapeutic targets. Here, we identify a convergent pathway common to genetic and environmental models of Parkinsonism that not only affects the brain but also systemically. Using integrated metabolomics, proteomics, and genome-scale metabolic modeling, we demonstrate that purine metabolism is dysregulated across models. Reverse genetic screening of key enzymes in this pathway mitigates locomotor deficits induced by neurotoxic pesticide exposure in Drosophila . These findings reveal a shared metabolic vulnerability in PD and highlight purine metabolism as a potential therapeutic target.