Pathogenic Mechanisms of Environmental Toxicants in Parkinson's Disease

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DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. The etiology of PD remains unknown. Epidemiological studies have revealed that exposure to environmental toxicants, including pesticides, increases the risk of PD. Many of these toxicants, such as rotenone, paraquat, and 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been shown to increase the levels of reactive oxygen species (ROS) and cause PD-like phenotypes in animals. These and other lines of evidence have implicated a crucial role for oxidative stress in PD pathogenesis. However, it is not known how environmental toxicant-induced oxidative stress leads to neuronal dysfunction and, ultimately, neuronal cell death. The long-term goal of this research is to elucidate the molecular mechanisms by which environmental toxicants cause neurodegeneration in PD. While only a very small percentage of PD cases are monogenic familial forms, molecular characterization of the identified familial PD proteins has revealed novel pathways involved in PD pathogenesis. DJ-1 is a recently identified PD gene whose mutations cause an early-onset, autosomal recessive form of familial PD. Accumulating evidence indicates that DJ-1 plays an essential role in protecting dopaminergic neurons against oxidative stress. This project will investigate the interaction between the familial PD gene DJ-1 and sporadic PD-associated environmental toxicants, and test the hypothesis that environmental toxicants cause oxidative damage to DJ-1, thereby contributing to the pathogenesis of sporadic PD in a manner similar to DJ-1 genetic mutations in causing familial PD. A combination of biochemical, proteomic, biophysical, cell biological, and molecular genetic approaches will be used to characterize the environmental toxicant-induced oxidative damage to DJ-1, examine the in vivo role of environmental toxicant-induced DJ-1 oxidation in PD pathogenesis, and determine the mechanisms by which environmental toxicants disrupt the DJ-1 neuroprotective pathway. Completion of this project should advance our understanding of the mechanistic role of environmental toxicants in neurodegeneration and help develop more effective therapies to treat PD. PUBLIC HEALTH RELEVANCE Project Narrative Although the etiology of Parkinson's disease (PD) remains unknown, there is compelling evidence that environmental toxicants, especially pesticides, are dominant risk factors in sporadic PD. The goal of the proposed research is to determine how environmental toxicants lead to neuronal dysfunction and, ultimately, neuronal cell death in PD. The results of the proposed studies will promote the discovery of new therapies for preventing and treating this devastating illness.