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Science 26 January 1996:
Vol. 271. no. 5248, pp. 515 - 518
DOI: 10.1126/science.271.5248.515
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Reports

Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis

Martina Wiedau-Pazos (1),  Joy J. Goto (1),  Shahrooz Rabizadeh,  Edith B. Gralla,  James A. Roe,  Michael K. Lee,  Joan S. Valentine (2),  Dale E. Bredesen (2)

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.


M. Wiedau-Pazos, J. J. Goto, E. B. Gralla, J. S. Valentine, Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
S. Rabizadeh, Interdepartmental Program for Neuroscience, University of California, Los Angeles, CA 90095, USA, and Program on Aging, La Jolla Cancer Research Foundation, La Jolla, CA 92037, USA.
J. A. Roe, Department of Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, USA.
M. K. Lee, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
D. E. Bredesen, Program on Aging, La Jolla Cancer Research Foundation, La Jolla, CA 92037, USA.
(1) These authors contributed equally to this report.
(2) To whom correspondence should be addressed.


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Selegiline Is Ineffective in a Collaborative Double-blind, Placebo-Controlled Trial for Treatment of Amyotrophic Lateral Sclerosis.
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L. L. Dugan, D. M. Turetsky, C. Du, D. Lobner, M. Wheeler, C. R. Almli, C. K.-F. Shen, T.-Y. Luh, D. W. Choi, and T.-S. Lin (1997)
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Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant.
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A Familial Amyotrophic Lateral Sclerosis-associated A4V Cu,Zn-Superoxide Dismutase Mutant Has a Lower Km for Hydrogen Peroxide. CORRELATION BETWEEN CLINICAL SEVERITY AND THE Km VALUE.
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Identification and Functional Expression of HAH1, a Novel Human Gene Involved in Copper Homeostasis.
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Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.
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PNAS 93, 14940-14944
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REVIEW {blacksquare} : Keeping Neurons Alive: The Molecular Control of Apoptosis (Part I.
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ALS: Molecular Clues to the Jigsaw Puzzle of Neuronal Degeneration.
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Bicarbonate Enhances Peroxidase Activity of Cu,Zn-Superoxide Dismutase. ROLE OF CARBONATE ANION RADICAL AND SCAVENGING OF CARBONATE ANION RADICAL BY METALLOPORPHYRIN ANTIOXIDANT ENZYME MIMETICS.
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Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase.
P. C. Wong, D. Waggoner, J. R. Subramaniam, L. Tessarollo, T. B. Bartnikas, V. C. Culotta, D. L. Price, J. Rothstein, and J. D. Gitlin (2000)
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