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

• Published in: Science (American Association for the Advancement of Science) 1998-09, Vol.281 (5384), p.1851-1854
• Main Authors: Bruijn, Lucie I., Houseweart, Megan K., Kato, Shinsuke, Anderson, Karen L., Anderson, Scott D., Ohama, Eisaku, Reaume, Andrew G., Scott, Rick W., Cleveland, Don W.
• Format: Article
• Language: English
• Subjects: Age Differences; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Animals; Antibodies; Astrocytes - enzymology; Astrocytes - ultrastructure; Axons; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease; Disease Progression; Enzymes; Female; Humans; Hydrogen Peroxide - metabolism; Inclusion Bodies - enzymology; Inclusion Bodies - ultrastructure; Male; Medical sciences; Mice; Mice, Transgenic; Motor neuron disease; Motor neurons; Motor Neurons - enzymology; Motor Neurons - pathology; Mutation; Mutation (Biology); Nerve Degeneration; Nervous system diseases; Neurology; Neurons; Oxidative Stress; Pathology; Rodents; Spinal cord; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Superoxides; Superoxides - metabolism; Toxicity; Transgenic animals
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.281.5384.1851

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.