Which mechanisms of pollutant-induced mitochondrial dysfunction cause dopaminergic neurodegeneration? - Parkinson’s disease (PD) affects one to two percent of the population over age 60. Many treatments are costly, and while they temporarily alleviate symptoms, none currently available slow progression. Therefore, understanding the mechanistic basis of PD is critical to inform both preventive and therapeutic efforts. Environmental factors are important contributors to PD, and laboratory, clinical, and epidemiological studies have demonstrated a role for several specific chemical exposures. All of these chemicals affect mitochondria. However, there is strong evidence for association with PD for only a few chemicals, and because relatively few people are exposed to significant amounts of those chemicals, they collectively likely explain only a small fraction of PD. Recent high-throughput toxicological screens have demonstrated that hundreds if not thousands of chemicals in commerce cause mitochondrial dysfunction and toxicity. It is not possible to test all of these thoroughly, and yet regulatory action requires clear toxicological data. How can we rationally prioritize these chemicals for testing? A way forward is suggested by the fact that although these chemicals are all mitotoxicants, they have multiple mechanisms of toxicity. These include inhibition of all four electron chain complexes, ATP synthase, and Krebs cycle enzymes; redox cycling; mitochondrial DNA damage; and uncoupling of ATP production from oxygen consumption. We propose to narrow the focus of efforts to identify chemicals that could contribute to PD, by clarifying which of the many mechanisms by which chemicals cause “mitochondrial dysfunction” can contribute to dopaminergic neurodegeneration. We will define which specific forms of mitochondrial dysfunction result in dopaminergic neurodegeneration. We will also test whether key downstream outcomes, oxidative stress and ATP depletion, are required for dopaminergic neurodegeneration. This additional layer of mechanistic understanding lends itself to high-throughput screening, and may be informative for therapeutic efforts. We will test the causality of specific forms of mitochondrial dysfunction by using pollutants that act by different mitotoxic mechanisms; by comparing the timeline of energetic and oxidative stress changes with neurodegeneration; and by rescue experiments. In order to examine this large number of exposures in an in vivo, yet rigorous and highly replicated fashion, we will work in the model organism Caenorhabditis elegans. We are developing novel strains of C. elegans that will permit us to carry out aging-related, in vivo assessments of cell type-specific changes to all of these parameters, in the same individuals. Overall, results from this work will serve to mechanistically delimit the landscape of chemical exposures that could contribute to PD, guiding regulatory guideline development as well as justifying additional future research in vertebrate models and epidemiological studies.
