| Among age-related neurodegenerative disorders, Parkinson's disease (PD) represents the best example for which oxidative stress and mitochondrial dysfunction have been implicated in disease pathogenesis. The etiology of PD remains unknown, yet recent epidemiological data have linked exposure to environmental chemicals, including pesticides, with an increased risk of developing the disease. One such example is paraquat (PQ), a widely used herbicide throughout the world that also has become increasingly popular in toxicant-based models of PD. PQ toxicity is believed to arise from the induction of oxidative stress caused by excessive generation of reactive oxygen species (ROS) via redox cycling reactions. Previous work in Dr. Patel's laboratory identified mitochondria as a major source of PQ-induced ROS production, although the underlying mechanisms in the brain remain undefined. Taken together, this comprehensive study addresses the hypothesis that imbalances in mitochondrial ROS metabolism leading to altered cellular redox status are contributing factors to PQ neurotoxicity. Steady state levels of glutathione and the enzymes responsible this anti-oxidant's utilization and regulation were dramatically altered in dopaminergic neurons with PQ treatment. In contrast with another model PD toxicant, 1-methyl-4-phenylpyridinium, the resultant changes in cellular redox environment were largely responsible for dopaminergic cell death in response to PQ. This study also utilized isolated mitochondria to identify unique mechanisms of PQ-induced ROS production in the brain. Specifically, the respiratory chain was a necessary component for ROS production by PQ and related redox cycling herbicides with complex III serving as the potential site of action. Furthermore, the ROS generating actions and neurotoxicity of PQ were mediated by the thioredoxin/peroxiredoxin system, which was identified as the major H2O2 detoxification pathway in brain mitochondria. Additionally, PQ itself could inhibit the activity of thioredoxin reductase, which correlated with compromised anti-oxidant efficiency in mitochondria following exposure to the herbicide. Given the potential consequences of PQ exposure identified in epidemiological studies and the herbicide's use in toxicant-based models of PD, these studies highlight the importance of mitochondrial contributions and identify unique redox mechanisms underlying PD-related dopaminergic cell death and neurogenerative processes. |
