Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis

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 subst...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 1996-01, Vol.271 (5248), p.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: Article
Language:English
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
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Description
Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.271.5248.515