Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis

Martina Wiedau-Pazos, Joy J. Goto, Shahrooz Rabizadeh, Edith B. Gralla, James A. Roe, Michael K. Lee, Joan S. Valentine, Dale E. Bredesen

Research output: Contribution to journalArticlepeer-review

649 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)515-518
Number of pages4
Issue number5248
StatePublished - Jan 26 1996

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