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Science 24 December 1999:
Vol. 286. no. 5449, pp. 2498 - 2500
DOI: 10.1126/science.286.5449.2498
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Reports

Induction of Nitric Oxide -- Dependent Apoptosis in Motor Neurons by Zinc-Deficient Superoxide Dismutase

Alvaro G. Estévez, 15* John P. Crow, 145* Jacinda B. Sampson, 125 Christopher Reiter, 12 Yingxin Zhuang, 1 Gloria J. Richardson, 1 Margaret M. Tarpey, 15 Luis Barbeito, 56 Joseph S. Beckman 1235dagger

Mutations in copper, zinc superoxide dismutase (SOD) have been implicated in the selective death of motor neurons in 2 percent of amyotrophic lateral sclerosis (ALS) patients. The loss of zinc from either wild-type or ALS-mutant SODs was sufficient to induce apoptosis in cultured motor neurons. Toxicity required that copper be bound to SOD and depended on endogenous production of nitric oxide. When replete with zinc, neither ALS-mutant nor wild-type copper, zinc SODs were toxic, and both protected motor neurons from trophic factor withdrawal. Thus, zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide.

1 Departments of Anesthesiology,
2 Biochemistry and Molecular Genetics,
3 Neurobiology, and
4 Pharmacology and Toxicology and the
5 Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
6 Sección Neurociencias, Facultad de Ciencias, Universidad de la República, Division Neurobiología Celular y Molecular, Instituto de Investigaciones Biologicas Clemente Estable, Montevideo, 11600 Uruguay.
*   These authors contributed equally to this paper.

dagger    To whom correspondence should be addressed. E-mail: joe.beckman{at}ccc.uab.edu

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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B. N Ames, I. Elson-Schwab, and E. A Silver (2002)
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   Abstract »    Full Text »    PDF »
Histidinyl Radical Formation in the Self-peroxidation Reaction of Bovine Copper-Zinc Superoxide Dismutase.
M. R. Gunther, J. A. Peters, and M. K. Sivaneri (2002)
J. Biol. Chem. 277, 9160-9166
   Abstract »    Full Text »    PDF »
Protein tyrosine nitration in mouse peritoneal macrophages activated in vitro and in vivo: evidence against an essential role of peroxynitrite.
S. PFEIFFER, A. LASS, K. SCHMIDT, and B. MAYER (2001)
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   Abstract »    Full Text »    PDF »
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M. A. Johnson, T. L. Macdonald, J. B. Mannick, M. R. Conaway, and B. Gaston (2001)
J. Biol. Chem. 276, 39872-39878
   Abstract »    Full Text »    PDF »
Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis.
J. C Desport, P. M Preux, L. Magy, Y. Boirie, J. M Vallat, and B. Beaufrere (2001)
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   Abstract »    Full Text »
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   Abstract »    Full Text »    PDF »
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L. P. Rowland and N. A. Shneider (2001)
N. Engl. J. Med. 344, 1688-1700
   Full Text »    PDF »
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X. F. Wang and M. S. Cynader (2001)
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   Abstract »    Full Text »    PDF »
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S. Vukosavic, L. Stefanis, V. Jackson-Lewis, C. Guegan, N. Romero, C. Chen, M. Dubois-Dauphin, and S. Przedborski (2000)
J. Neurosci. 20, 9119-9125
   Abstract »    Full Text »    PDF »
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S. Hortelano, A. Castrillo, A. M. Alvarez, and L. Bosca (2000)
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   Abstract »    Full Text »    PDF »
Role of Nitric Oxide and Superoxide in Acute Cardiac Allograft Rejection in Rats.
E. Akizuki, T. Akaike, S. Okamoto, S. Fujii, Y. Yamaguchi, M. Ogawa, and H. Maeda (2000)
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   Abstract »    Full Text »
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   Abstract »    Full Text »    PDF »
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P. Hardy, I. Dumont, M. Bhattacharya, X. Hou, P. Lachapelle, D. R. Varma, and S. Chemtob (2000)
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   Abstract »    Full Text »    PDF »
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T. L. Williamson, L. B. Corson, L. Huang, A. Burlingame, J. Liu, L. I. Bruijn, D. W. Cleveland;, J. S. Beckman, J. P. Crow, and A. G. Estévez; (2000)
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   Full Text »
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S. I. Liochev and I. Fridovich (2000)
J. Biol. Chem. 275, 38482-38485
   Abstract »    Full Text »    PDF »
Copper,Zinc Superoxide Dismutase as a Univalent NO- Oxidoreductase and as a Dichlorofluorescin Peroxidase.
S. I. Liochev and I. Fridovich (2001)
J. Biol. Chem. 276, 35253-35257
   Abstract »    Full Text »    PDF »
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.
H. Zhang, J. Joseph, M. Gurney, D. Becker, and B. Kalyanaraman (2002)
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   Abstract »    Full Text »    PDF »
Tyrosine Nitration by Peroxynitrite Formed from Nitric Oxide and Superoxide Generated by Xanthine Oxidase.
T. Sawa, T. Akaike, and H. Maeda (2000)
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   Abstract »    Full Text »    PDF »
Superoxide Reacts with Nitric Oxide to Nitrate Tyrosine at Physiological pH via Peroxynitrite.
C. D. Reiter, R.-J. Teng, and J. S. Beckman (2000)
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