INCREASED 3-NITROTYROSINE AND OXIDATIVE DAMAGE IN MICE WITH A HUMAN COPPER ZINC SUPEROXIDE-DISMUTASE MUTATION/

Mutations in copper/zinc superoxide dismutase (SOD1) cause a subset of cases of autosomal dominant familial amyotrophic lateral sclerosis (F ALS), Transgenic mice that express these point mutations develop progr essive 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 abi lity of the mutant SOD1 to generate OI-I radicals or to facilitate per oxynitrite-mediated nitration of proteins, We found significant increa ses in concentrations of 3-nitrotyrosine, a marker of peroxyitrite-med iated nitration, in upper and lower spinal cord and in cerebra cortex of transgenic mice with the FALS-associated G93A mutation, Malondialde hyde, a marker of lipid peroxidation, was increased in cerebral cortex . 3-Nitrotyrosine-, heme oxygenase-1-, and malondialdehyde-modified pr otein immunoreactivities were increased throughout SOD1 transgenic mic e spinal cord but particularly within motor neurons. These results sug gest that the gain-of-function of at least one mutant SOD1 associated with FALS involves increased protein nitration and oxidative damage, w hich may play a role in neuronal degeneration.