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

• Published in: The Journal of biological chemistry 2007-06, Vol.282 (22), p.16329-16335
• Main Authors: Taylor, David M., Gibbs, Bernard F., Kabashi, Edor, Minotti, Sandra, Durham, Heather D., Agar, Jeffrey N.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Disease Models, Animal; Erythrocytes - enzymology; Erythrocytes - pathology; Humans; Inclusion Bodies - enzymology; Inclusion Bodies - genetics; Inclusion Bodies - pathology; Mice; Mice, Transgenic; Motor Neurons - enzymology; Motor Neurons - pathology; Mutation, Missense; Oxidation-Reduction; Protein Processing, Post-Translational; Rabbits; Spinal Cord - enzymology; Spinal Cord - pathology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Tryptophan - genetics; Tryptophan - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M610119200

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.