Manganese superoxide dismutase overexpression attenuates MPTP toxicity.
There is substantial evidence implicating mitochondrial dysfunction and free radical generation in the neurotoxicity of MPTP. Manganese superoxide dismutase (MnSOD) is the primary antioxidant enzyme protecting against superoxide radicals produced within mitochondria. Overexpression of human MnSOD in transgenic mice resulted in increased MnSOD localized to mitochondria in neurons and a 50% increase in total MnSOD activity in brain homogenates. We found that MPTP toxicity was significantly attenuated in the MnSOD transgenic mice which overexpress the human manganese superoxide dismutase gene, with these mice showing threefold greater dopamine levels than controls following MPTP. There were no alterations in MPP+ levels, suggesting that the effects were not due to altered metabolism of MPTP. A significant increase in 3-nitrotyrosine levels was seen in littermate controls but not in transgenic mice overexpressing human MnSOD. These results provide further evidence implicating mitochondrial dysfunction and oxidative damage in the pathogenesis of MPTP neurotoxicity.
Klivenyi
P
P
Neurochemistry Laboratory, Massachusetts General Hospital, Boston, USA.
St Clair
D
D
Wermer
M
M
Yen
H C
HC
Oberley
T
T
Yang
L
L
Flint Beal
M
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000201:enzymology / Q000648:ultrastructure; D009474:Neurons / Q000201:enzymology / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
D015259:Dopamine Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D013482:Superoxide Dismutase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine