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Increased 3‐nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation
Author(s) -
Ferrante Robert J.,
Shinobu Leslie A.,
Schulz Jörg B.,
Matthews Russell T.,
Thomas Craig E.,
Kowall Neil W.,
Gurney Mark E.,
Beal M. Flint
Publication year - 1997
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410420309
Subject(s) - sod1 , peroxynitrite , nitrotyrosine , superoxide dismutase , amyotrophic lateral sclerosis , malondialdehyde , chemistry , oxidative stress , lipid peroxidation , endocrinology , biochemistry , medicine , microbiology and biotechnology , biology , superoxide , enzyme , nitric oxide synthase , disease
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.