The long-term goal of this proposal is to determine the mechanisms of mitochondrial oxidative stress contributing to dopaminergic neuron death in Parkinson's disease (PD). Both environmental and genetic risk factors of PD are independently capable of producing oxidative stress and mitochondrial dysfunction. Recent epidemiogical evidence has linked exposure to pesticides present in the environment with increased risk of developing neurodegenerative diseases, including PD. Of particular interest is paraquat, a bipyridyl herbicide capable of generating reactive oxygen species (ROS). With implications of paraquat and other redox cycling agents as risk factors in disease development and as models of PD, there is a critical need to understand the biochemical mechanisms of toxicity in the brain. It is hypothesized that mitochondria act as a major cellular site in mediating ROS production due to redox cycling agents. The hypothesis predicts that redox cycling agents are capable of using mitochondrial pathways to generate ROS, while also decreasing rates of ROS consumption by altering the efficiency of mitochondrial anti-oxidant defense mechanisms. Additionally, ablated expression of the putative anti-oxidant PD gene, DJ-1, is hypothesized to exacerbate changes in mitochondrial ROS metabolism (production and consumption) in response to redox cycling agents. This proposal will utilize isolated brain mitochondria and dopaminergic cell culture models in conjunction with a diversity of tools and techniques that includes a novel polarographic method enabling the real-time detection of quantifiable steady-state concentrations of ROS.
Specific aim #1 will determine specific mitochondrial mechanisms involved in ROS productin induced by redox cycling agents.
Specific aim #2 will identify the contributions of molecular systems in the removal of ROS by mitochondria. In addition, which anti-oxidant systems are compromised after exposure to redox cycling agents will be assessed. Lastly, specific aim #3 will examine the interactions of redox cycling agents and PD genetic factors in mechanisms of ROS production and consumption in mitochondria.
This research can advance our understanding of the mitochondrial contributions to oxidative damage leading to neuronal death in PD and suggest novel therapeutic strategies for rescuing neurons from neurodegeneration relating to environmental factors. Additionally, this line of investigation may explain PD arising from exposure to redox cycling agents present both in the environment and endogenously in conjunction with increased susceptibility resulting from genetic factors. ? ? ?
| Drechsel, Derek A; Patel, Manisha (2010) Respiration-dependent H2O2 removal in brain mitochondria via the thioredoxin/peroxiredoxin system. J Biol Chem 285:27850-8 |
| Drechsel, Derek A; Patel, Manisha (2009) Differential contribution of the mitochondrial respiratory chain complexes to reactive oxygen species production by redox cycling agents implicated in parkinsonism. Toxicol Sci 112:427-34 |
