Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis
M Wiedau-Pazos, JJ Goto, S Rabizadeh, EB Gralla… - Science, 1996 - science.org
Science, 1996•science.org
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 …
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 …
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.
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