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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS037345-05
Application #
6539968
Study Section
Neurology A Study Section (NEUA)
Program Officer
Oliver, Eugene J
Project Start
1998-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$119,350
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
Teismann, Peter; Tieu, Kim; Cohen, Oren et al. (2003) Pathogenic role of glial cells in Parkinson's disease. Mov Disord 18:121-9
Teismann, P; Vila, M; Choi, D-K et al. (2003) COX-2 and neurodegeneration in Parkinson's disease. Ann N Y Acad Sci 991:272-7
Wu, Du-Chu; Teismann, Peter; Tieu, Kim et al. (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc Natl Acad Sci U S A 100:6145-50
Guegan, Christelle; Przedborski, Serge (2003) Programmed cell death in amyotrophic lateral sclerosis. J Clin Invest 111:153-61

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