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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M610119200