Comparative Proteomic Analysis of Environmental and Genetic Models of Parkinson’s Disease Highlights the Role of Purine Metabolism

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 <i>Drosophila</i> . These findings reveal a shared metabolic vulnerability in PD and highlight purine metabolism as a potential therapeutic target.