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.
