MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is used extensively in various mammalian species to produce an experimental model of Parkinson's disease (PD), a common and disabling neurodegenerative disorder of unknown cause. A variety of markers and indices in PD patents and animal models indicate involvement of oxygen free radicals and oxidative stress in the pathogenesis of PD. Preliminary studies indicate a potential pivotal role for nitric oxide in the pathogenesis of MPTP neurotoxicity and that this neurotoxicity may be mediated, in part, through the reaction of NO with the superoxide anion to form peroxynitrate. NO, or peroxynitrate, can activate amongst other responses, poly (ADP-ribose) polymerase (PARP), which may lead to the loss of cellular NAD+ and ATP, resulting in acute cell injury and death. These events may be crucial in both short-and long- term deleterious effects of MPTP. However, it is unclear whether this pathway (PARP activation and NAD+ loss) caused by these toxic effects is solely responsible for cell death, or whether other pathways such as caspase activations, which involves cleavage of PARP and other substrates may also contribute to neuronal injury. Accordingly, experiments are proposed to further clarify the role of NO in MPTP neurotoxicity and to investigate the source of superoxide anion generation and the downstream targets of NO, superoxide anion and peroxynitrate in MPTP neurotoxicity.
In Specific Aim #1 we will determine the role and source of nitric oxide in MPTP-induced dopaminergic cell death.
In Specific Aim #2 we will determine the role of cytosolic versus mitochondrial superoxide anion generation in MPTP-induced dopaminergic cell death.
In Specific Aim #3 we will determine and clarify the role of poly (ADP-ribose) polymerase (PARP) activation and cleavage in MPTP-induced dopaminergic cell death.
In Specific Aim #4 we will identify dynamically regulated genes in the rodent MPTP model of PD. Potential oxidative post-translational modification of critical enzymes and proteins that regulate the disposition of dopamine in the nigrostriatal pathway [e.g., tyrosine hydroxylase (TH), dopamine transporter (DAT) and the monoamine vesicular transporter (VMAT)] will be examined following MPTP intoxication as well. Oxidative damage, potentially through mitochondrial defects, excess or aberrant NO generation and/or monoamine metabolism has been implicated in the pathogenesis of PD. Clarification and understanding the molecular mechanisms by which oxidants induce neuronal damage, interact with PARP and caspase activation cascade and modify gene regulation, may provide novel therapeutics and targets to prevent the toxic effects of MPTP and the degenerative process of PD.
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