The PI is a clinically trained neurologist specializing in Parkinson's disease (PD). The PI has been studying the molecular mechanism of I -methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (MPTP), a toxin that damages substantia nigra (SN) dopamine (DA) neurons as seen in PD. The PI's work has provided compelling evidence that both superoxide radicals and nitric oxide (NO) are implicated in MPTP's toxicity. Both species are modestly reactive, but can combine to produce the highly reactive tissue-damaging peroxynitrite. To elucidate the source of N0 that participates in MPTP's toxicity, Specific Aim (SA)-I will compare the effects of MPTP on SN DA neurons of mutant mice deficient in neuronal, inducible, or endothelial NO synthase (NOS), the three isoforms of NOS. To demonstrate the production of peroxynitrite following MPTP administration, SA-II will quantify striatal and midbrain levels of nitrotyrosine, a stable fingerprint of peroxynitrite's deleterious effects on proteins, at different time-points and doses of MPTP. The requirement for superoxide, NO, and MPTP's active metabolite, 1- methyl-4-phenylpyridinium in protein nitrotyrosine formation, as well as its specificity for DA neurons will also be examined. To define the cell groups and organelles preferentially tyrosine-nitrated, SA-III will ascertain the cellular and subcellular distribution of nitrotyrosine immunoreactivity in the mouse midbrain after MPTP administration. To examine the potential biological consequences of protein tyrosine nitration, SA-IV will assess whether candidate proteins, tyrosine hydroxylase and manganese superoxide dismutase, are nitrated after MPTP administration. The catalytic activity of these enzymes and the search for other proteins that are tyrosine-nitrated after MPTP administration will also be undertaken. This proposal contains a comprehensive set of experiments, which should provide important insights into the role of NO in MPTP toxicity. It should also shed light on the mechanism(s) of neurodegeneration in PD.
| Przedborski, Serge; Ischiropoulos, Harry (2005) Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson's disease. Antioxid Redox Signal 7:685-93 |
| Przedborski, Serge (2005) Pathogenesis of nigral cell death in Parkinson's disease. Parkinsonism Relat Disord 11 Suppl 1:S3-7 |
| Vila, Miquel; Przedborski, Serge (2004) Genetic clues to the pathogenesis of Parkinson's disease. Nat Med 10 Suppl:S58-62 |
| Przedborski, Serge; Tieu, Kim; Perier, Celine et al. (2004) MPTP as a mitochondrial neurotoxic model of Parkinson's disease. J Bioenerg Biomembr 36:375-9 |
| Tieu, Kim; Perier, Celine; Vila, Miquel et al. (2004) L-3-hydroxyacyl-CoA dehydrogenase II protects in a model of Parkinson's disease. Ann Neurol 56:51-60 |
| Crocker, Stephen J; Smith, Patrice D; Jackson-Lewis, Vernice et al. (2003) Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson's disease. J Neurosci 23:4081-91 |
| Tieu, Kim; Ischiropoulos, Harry; Przedborski, Serge (2003) Nitric oxide and reactive oxygen species in Parkinson's disease. IUBMB Life 55:329-35 |
| Przedborski, Serge; Jackson-Lewis, Vernice; Vila, Miquel et al. (2003) Free radical and nitric oxide toxicity in Parkinson's disease. Adv Neurol 91:83-94 |
| Tieu, Kim; Perier, Celine; Caspersen, Casper et al. (2003) D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest 112:892-901 |
| Teismann, Peter; Tieu, Kim; Choi, Dong-Kug et al. (2003) Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proc Natl Acad Sci U S A 100:5473-8 |
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