title: Tryptophan 32 potentiates aggregation and cytotoxicity of a copper/zinc superoxide dismutase mutant associated with familial amyotrophic lateral sclerosis.
abstract: 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.
authors: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Sheldon Biotechnology Centre, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors: David M
authors: DM
authors: Taylor
authors: Bernard F
authors: BF
authors: Gibbs
authors: Edor
authors: E
authors: Kabashi
authors: Sandra
authors: S
authors: Minotti
authors: Heather D
authors: HD
authors: Durham
authors: Jeffrey N
authors: JN
authors: Agar
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000201:enzymology / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism
chemical_list: C000606290:SOD1 protein, human; D014364:Tryptophan; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1