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J. Biol. Chem., Vol. 282, Issue 22, 16329-16335, June 1, 2007

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Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis^*

David M. Taylor¹, Bernard F. Gibbs, Edor Kabashi², Sandra Minotti, Heather D. Durham³, and Jeffrey N. Agar^¶4

From the Department of Neurology and Neurosurgery, Montreal Neurological Institute and Sheldon Biotechnology Centre, McGill University, Montreal, Quebec H3A 2B4, Canada and ^¶Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454

One familial form of the neurodegenerative disease, amyotrophic lateral sclerosis, is caused by gain-of-function mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1). This study provides in vivo evidence that normally occurring oxidative modification to SOD-1 promotes aggregation and toxicity of mutant proteins. The oxidation of Trp-32 was identified as a normal modification being present in both wild-type enzyme and SOD-1 with the disease-causing mutation, G93A, isolated from erythrocytes. Mutating Trp-32 to a residue with a slower rate of oxidative modification, phenylalanine, decreased both the cytotoxicity of mutant SOD-1 and its propensity to form cytoplasmic inclusions in motor neurons of dissociated mouse spinal cord cultures.

Received for publication, October 30, 2006

^* This work was funded by a research grant from ALS Association (to H. D. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a McGill faculty of medicine studentship.

² Recipient of a Canadian Institutes of Health Research fellowship awarded on behalf of the Amyotrophic Lateral Sclerosis Society of Canada.

³ To whom correspondence may be addressed: Dept. of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University St., Montreal, Quebec H3A 2B4, Canada. Tel.: 514-398-8509; Fax: 514-398-1509; E-mail: heather.durham{at}mcgill.ca. ⁴Supported by a Muscular Dystrophy Association career development grant, a Conrad Harrington fellowship, and a Jeanne Timmons fellowship. To whom correspondence may be addressed: Dept. of Chemistry, Brandeis University, Rosenstiel Biomedical Science Bldg., 415 South St., Waltham, MA 02454. Tel.: 781-736-2425; Fax: 781-736-2516; E-mail: agar{at}brandeis.edu.

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