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 (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.
Ferrante
R J
RJ
Geriatric Research Education Clinical Center, VA Medical Center, Bedford, MA, USA.
Shinobu
L A
LA
Schulz
J B
JB
Matthews
R T
RT
Thomas
C E
CE
Kowall
N W
NW
Gurney
M E
ME
Beal
M F
MF
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
C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D003300:Copper; D006419:Heme Oxygenase (Decyclizing); D013482:Superoxide Dismutase; D015032:Zinc