PMID:9462746

Citation	Melov, S, Schneider, JA, Day, BJ, Hinerfeld, D, Coskun, P, Mirra, SS, Crapo, JD and Wallace, DC (1998) A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nat. Genet. 18:159-63
Abstract	Reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemic heart disease, Alzheimer disease, Parkinson disease and aging. ROS are generated by mitochondria as the toxic by-products of oxidative phosphorylation, their energy generating pathway. Genetic inactivation of the mitochondrial form of superoxide dismutase in mice results in dilated cardiomyopathy, hepatic lipid accumulation and early neonatal death. We report that treatment with the superoxide dismutase (SOD) mimetic Manganese 5, 10, 15, 20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) rescues these Sod2tm1Cje(-/-) mutant mice from this systemic pathology and dramatically prolongs their survival. The animals instead develop a pronounced movement disorder progressing to total debilitation by three weeks of age. Neuropathologic evaluation reveals a striking spongiform degeneration of the cortex and specific brain stem nuclei associated with gliosis and intramyelinic vacuolization similar to that observed in cytotoxic edema and disorders associated with mitochondrial abnormalities such as Leighs disease and Canavans disease. We believe that due to the failure of MnTBAP to cross the blood brain barrier progressive neuropathology is caused by excessive mitochondrial production of ROS. Consequently, MnTBAP-treated Sod2tm1Cje(-/-) mice may provide an excellent model for examining the relationship between free radicals and neurodegenerative diseases and for screening new drugs to treat these disorders.
Links	PubMed Online version:10.1038/ng0298-159
Keywords	Animals; Brain/pathology; Brain Stem/pathology; Brain Stem/ultrastructure; Cerebral Cortex/pathology; Cerebral Cortex/ultrastructure; DNA, Mitochondrial/genetics; Free Radical Scavengers/pharmacology; Humans; Lipid Metabolism; Liver/metabolism; Metalloporphyrins/pharmacology; Mice; Mice, Knockout; Mitochondria/enzymology; Neurodegenerative Diseases/drug therapy; Neurodegenerative Diseases/genetics; Neurodegenerative Diseases/pathology; Neurons/pathology; Superoxide Dismutase/deficiency; Superoxide Dismutase/genetics; Survival Rate; Trigeminal Nuclei/pathology; Trigeminal Nuclei/ultrastructure; Vacuoles/pathology; Vacuoles/ultrastructure
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