Grant: China-Canada Joint Health Research Initiative

SOD1 is a free radical scavenger in the body. Mutations in the SOD1 gene have been reported in about 2% of patients with amyotrophic lateral sclerosis (ALS), a disease characterized by loss of motor neurons. Transgenic animals expressing the human SOD1 mutations develop ALS-like symptoms. Surprisingly, studies have overwhelmingly demonstrated that these mutant SOD1 enzymes cause motoneuron degeneration by a gain of toxic property, rather than a loss of superoxide dismutation function. The nature of the gain-of-function toxicity in mutant SOD1 is not clear. Our recent preliminary data suggest that SOD1 oxidation plays a role in the pathogenesis of ALS. Here we propose to test the hypothesis that SOD1 oxidation is the earliest event that triggers SOD1 aggregation and induces motor neuron death in ALS. Specifically, we will test: 1) SOD1 oxidation correlates with the formation of SOD1 aggregates in animal models of ALS and in ALS patients; 2) Mutant SOD1 proteins are not toxic unless they are oxidized, and oxidized wild type SOD1 protein becomes toxic to motor neurons; 3) mutant SOD1 proteins are more prone to oxidation in oxidative stress than wild-type SOD1; 4) Anti-oxidation prevents oxidized SOD1-induced motor neuron death. If this hypothesis is proven, the outcome of the proposal would support that ALS is virtually an SOD1 disease and implicate a role of oxidized WT SOD1 in sporadic ALS. As a result, this would open up a new avenue for the study of sporadic ALS.