Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis

• Published in: Science (American Association for the Advancement of Science) Vol. 271; no. 5248; pp. 515 - 518
• Main Authors: Wiedau-Pazos, Martina, Goto, Joy J., Rabizadeh, Shahrooz, Gralla, Edith B., Roe, James A., Lee, Michael K., Valentine, Joan S., Bredesen, Dale E.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 26.01.1996; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Active sites; Adducts; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Animals; Apoptosis; Apoptosis - drug effects; Binding Sites; Biochemistry; Biological and medical sciences; Catalysis; Cell culture techniques; Cell Line; Chelating Agents - pharmacology; Copper - metabolism; Cyclic N-Oxides - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Ditiocarb - pharmacology; Enzymes; Genes; Genetic aspects; Heredity; Humans; Hydrogen Peroxide - metabolism; Medical sciences; Motor neurons; Mutation; Neurological disorders; Neurology; Observation; Oxidation; Oxidation-Reduction; Penicillamine - pharmacology; Rats; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Yeasts; Human; Nervous system diseases; Enzyme; Pathogenesis; Amyotrophic lateral sclerosis; Superoxide dismutase; Genetic disease; Enzymatic activity; Gene; Central nervous system disease; Genetics; Degenerative disease; Oxidoreductases; Mutation; Spinal cord disease
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.271.5248.515

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.