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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / metabolism*
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Disease Models, Animal
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Erythrocytes / enzymology
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Erythrocytes / pathology
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Humans
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Inclusion Bodies / enzymology*
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Inclusion Bodies / genetics
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Inclusion Bodies / pathology
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Mice
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Mice, Transgenic
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Motor Neurons / enzymology*
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Motor Neurons / pathology
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Mutation, Missense*
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Oxidation-Reduction
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Protein Processing, Post-Translational*
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Rabbits
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Spinal Cord / enzymology
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Spinal Cord / pathology
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism*
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Superoxide Dismutase-1
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Tryptophan / genetics
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Tryptophan / metabolism
Substances
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SOD1 protein, human
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Tryptophan
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1