Role of Nitric Oxide in MPTP-Induced Dopaminergic Neuron Degeneration
Annual rept. 1 Sep 2001-31 Aug 2002
COLUMBIA UNIV NEW YORK
Pagination or Media Count:
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 Parkinsons 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.
- Medicine and Medical Research