title: Loss of oxidation-reduction specificity in amyotrophic lateral sclerosis-associated CuZnSOD mutants.
abstract: Both transgenic mouse and cell culture models of familial amyotrophic lateral sclerosis (FALS) support a gain-of-function effect for the mutations in copper-zinc superoxide dismutase (CuZnSOD) associated with FALS, but the nature of the function gained remains incompletely characterized. We previously reported an enhanced peroxidase activity for FALS-associated CuZnSOD mutants. Because one of the targets of such activity is CuZnSOD itself, we examined peroxide-mediated inactivation of wild-type and mutant CuZnSODs, and found that the mutants are more readily inactivated. Inactivation of the mutants was associated with fragmentation, which did not occur in the wild-type enzyme under these conditions. Furthermore, the reduction of the FALS-associated mutants by ascorbate was enhanced markedly when compared to the wild-type enzyme. The visible spectra of the mutants showed a consistent blue shift of the peak at 680 nm in the wild-type enzyme, suggesting an alteration in copper-site geometry. These results extend previous studies demonstrating enhanced peroxidase activity in the mutants, and suggest that the toxic function that leads to motor neuron degeneration may result from a loss of specificity of the redox reactions catalyzed by CuZnSOD.
authors.affiliation: Program on Aging, The Burnham Institute, La Jolla, CA 92037, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cafe
authors.forename: M P
authors.initials: MP
authors.lastname: Testa
authors.forename: P J
authors.initials: PJ
authors.lastname: Sheldon
authors.forename: W P
authors.initials: WP
authors.lastname: French
authors.forename: L M
authors.initials: LM
authors.lastname: Ellerby
authors.forename: D E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D019943:Amino Acid Substitution; D006801:Humans; D007700:Kinetics; D016472:Motor Neuron Disease / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D013053:Spectrophotometry; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D013482:Superoxide Dismutase