title: Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis.
abstract: A subset of individuals with familial amyotrophic lateral sclerosis (FALS) possesses dominantly inherited mutations in the gene that encodes copper-zinc superoxide dismutase (CuZnSOD). A4V and G93A, two of the mutant enzymes associated with FALS, were shown to catalyze the oxidation of a model substrate (spin trap 5,5'-dimethyl-1-pyrroline N-oxide) by hydrogen peroxide at a higher rate than that seen with the wild-type enzyme. Catalysis of this reaction by A4V and G93A was more sensitive to inhibition by the copper chelators diethyldithiocarbamate and penicillamine than was catalysis by wild-type CuZnSOD. The same two chelators reversed the apoptosis-inducing effect of mutant enzymes expressed in a neural cell line. These results suggest that oxidative reactions catalyzed by mutant CuZnSOD enzymes initiate the neuropathologic changes in FALS.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles 90095, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wiedau-Pazos
authors.forename: J J
authors.initials: JJ
authors.lastname: Goto
authors.forename: S
authors.initials: S
authors.lastname: Rabizadeh
authors.forename: E B
authors.initials: EB
authors.lastname: Gralla
authors.forename: J A
authors.initials: JA
authors.lastname: Roe
authors.forename: M K
authors.initials: MK
authors.lastname: Lee
authors.forename: J S
authors.initials: JS
authors.lastname: Valentine
authors.forename: D E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000494:pharmacology; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D003497:Cyclic N-Oxides; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D003300:Copper; D004050:Ditiocarb; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D010396:Penicillamine