Role of Nitric Oxide in MPTP-Induced Dopaminergic Neuron Degeneration
Abstract
We investigated the role of nitric oxide (NO) in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced dopaminergic (DA) neuron death in this mouse model of Parkinson's Disease (PD). Our previous work demonstrated that the superoxide radical is involved in the MPTP neurotoxic process in SNpc DA neurons. SNpc DA neurons in mice overexpressing superoxide dismutase (SOD1) were protected against MPTP-induced degeneration. Since the superoxide radical does not act alone, based on the oxidative stress hypothesis, in Specific Aim I, we demonstrated that neuronal NOS (nNOS) and inducible NOS (iNOS) are both players in MPTP-induced neurotoxicity to SNpc DA neurons. In Specific Aim II, we show that while nNOS has a role in MPTP toxicity to SNpc DA neurons, iNOS is the principle culprit here due to its upregulation in activated microglia. Peroxynitrite-induced alterations in protein tyrosine residues were demonstrated in striatum and ventral mibrain of MPTP-treated mice by measurement of nitrotyrosine, orthotyrosine and o,o-dityrosine in Specific Aim III. Furthermore, Specific Aim IV showed that proteins important to normal function in SNpc DA neurons, tyrosine hydroxylase and alpha-synuclein, are nitrated following MPTP exposure. We conclude that the superoxide radical and NO act in concert to initiate and propagate DA neuronal death in the SNpc of MPTP-treated mice and in PD patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2002
- Accession Number
- ADA416386
Entities
People
- Serge Przedborski
Organizations
- Columbia University