Aggregation and Motor Neuron Toxicity of an ALS-Linked SOD1 Mutant Independent from Wild-Type SOD1

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Science  18 Sep 1998:
Vol. 281, Issue 5384, pp. 1851-1854
DOI: 10.1126/science.281.5384.1851

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Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)–linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties. In testing the disease mechanism, both elimination and elevation of wild-type SOD1 were found to have no effect on mutant-mediated disease, which demonstrates that the use of SOD mimetics is unlikely to be an effective therapy and raises the question of whether toxicity arises from superoxide-mediated oxidative stress. Aggregates containing SOD1 were common to disease caused by different mutants, implying that coaggregation of an unidentified essential component or components or aberrant catalysis by misfolded mutants underlies a portion of mutant-mediated toxicity.

  • * Present address: Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, CT 06492–7660, USA.

  • To whom correspondence should be addressed. E-mail: dcleveland{at}

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