title: Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation.
abstract: Mutations in copper/zinc superoxide dismutase (SOD1) cause a subset of cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). Transgenic mice that express these point mutations develop progressive paralysis and motor neuron loss thought to be caused by a gain-of-function of the enzyme. The gain-of-function may be an enhanced ability of the mutant SOD1 to generate .OH radicals or to facilitate peroxynitrite-mediated nitration of proteins. We found significant increases in concentrations of 3-nitrotyrosine, a marker of peroxynitrite-mediated nitration, in upper and lower spinal cord and in cerebral cortex of transgenic mice with the FALS-associated G93A mutation. Malondialdehyde, a marker of lipid peroxidation, was increased in cerebral cortex. 3-Nitrotyrosine-, heme oxygenase-1-, and malondialdehyde-modified protein immunoreactivities were increased throughout SOD1 transgenic mice spinal cord but particularly within motor neurons. These results suggest that the gain-of-function of at least one mutant SOD1 associated with FALS involves increased protein nitration and oxidative damage, which may play a role in neuronal degeneration.
authors.affiliation: Geriatric Research Education Clinical Center, VA Medical Center, Bedford, MA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: L A
authors.initials: LA
authors.lastname: Shinobu
authors.forename: J B
authors.initials: JB
authors.lastname: Schulz
authors.forename: R T
authors.initials: RT
authors.lastname: Matthews
authors.forename: C E
authors.initials: CE
authors.lastname: Thomas
authors.forename: N W
authors.initials: NW
authors.lastname: Kowall
authors.forename: M E
authors.initials: ME
authors.lastname: Gurney
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology*; D003300:Copper / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics*; D008822:Mice, Transgenic / Q000235:genetics*; D016472:Motor Neuron Disease / Q000201:enzymology; D017354:Point Mutation; D011485:Protein Binding; D013116:Spinal Cord / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D003300:Copper; D006419:Heme Oxygenase (Decyclizing); D013482:Superoxide Dismutase; D015032:Zinc