AGGREGATION AND MOTOR-NEURON TOXICITY OF AN ALS-LINKED SOD1 MUTANT INDEPENDENT FROM WILD-TYPE SOD1

Analysis of transgenic mice expressing familiar amyotrophic Lateral sc lerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD 1) have shown that motor neuron death arises from a mutant-mediated to xic property or properties. In testing the disease mechanism, both eli mination and elevation of wild-type SOD1 were found to have no effect on mutant-mediated disease, which demonstrates that the use of SOD mim etics is unlikely to be an effective therapy and raises the question o f whether toxicity arises from superoxide-mediated oxidative stress. A ggregates containing SOD1 were common to disease caused by different m utants, implying that coaggregation of an unidentified essential compo nent or components or aberrant catalysis by misfolded mutants underlie s a portion of mutant-mediated toxicity.