Parkinson's Disease (PD) is the second most common neurodegenerative disorder and afflicts approximately 1% of the population over 60. The etiology of PD remains elusive despite significant recent research advances, but both environmental and genetic factors are thought to contribute in the majority of cases of sporadic disease. Current existing PD models are either genetic, based on disease associated mutations in single loci, or toxicant-induced, based on a small handful of compounds that elicit symptoms and pathology similar to disease features in humans on physiological, cellular and molecular levels. Genetic and toxicant models of PD both implicate oxidative stress, protein folding defects and proteosome dysfunction as underlying causes of the disease; however, the specific relationships between the affected pathways in these different models remain largely unexplored. Furthermore, there is a dearth of information regarding how gene environment interactions contribute to disease pathogenesis. To begin to address these outstanding questions, we propose to develop a toxicant-based model of PD in the model organism Drosophila melanogaster. This in vivo model is based on our preliminary studies that have demonstrated acute toxicity and behavioral deficits in flies treated with the prototypical systemic complex I inhibitor compound, rotenone. Once operational, this model will take advantage of the extensive preexisting genetic and molecular tools available in flies, as well as the Drosophila genetic PD models in order to better characterize genetic contributions to environmental insults and pathways resulting in neurodegeneration. For this application, our specific aims are: (1) to characterize chronic, subacute dose-response profiles in flies treated with complex I inhibitor toxicant compounds, and (2) to characterize dopaminergic neuron loss induced by complex I toxicant administration by neuronal subtype-specific analysis. As a result of this project, our future plans and Phase II SBIR expectations include using this Drosophila toxicant-induced PD model for in vivo compound screening for therapeutic drug discovery and the identification of validated targets through genetic analysis of enhancers and suppressors.
