Pyruvate protects motor neurons expressing mutant superoxide dismutase I against copper toxicity

Mutations in the copper/zinc superoxide dismutase (SODI) gene are known to be responsible for familial amyotrophic lateral sclerosis. Alteration of metal binding properties of mutant SODI has been proposed to play a role in the pathogenesis of amyotrophic lateral sclerosis.We investigated the toxic effects of excess extracellular copper on motor neuronal cells expressing human mutant SODI (G93A), and evaluated the neuroprotective effects of energy metabolism intermediates or cofactors. Motoneuron neuroblastoma hybrid (VSC 4.1) cells expressing mutant SODI, when treated with copper chloride, showed reduced viability and increased levels of endogenous peroxides. Moreover, this copper induced toxicity was attenuated by a free radical scavenger, a caspase inhibitor, or a calpain inhibitor. Of the energy metabolism intermediates examined, pyruvate significantly reduced the death and production of reactive oxygen species in cells expressing mutant SODI. Our data suggest that pyruvate could be of therapeutic value in some forms of familial amyotrophic lateral sclerosis. (c) 2005 Lippincott Williams & Wilkins.