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.