Oxidative stress causes abnormal accumulation of familial amyotrophic lateral sclerosis-related mutant SOD1 in transgenic Caenorhabditis elegans

Mutations in the Cu/Zn superoxide dismutase (SOD1) genes are present in sim ilar to 20% of families suffering from familial amyotrophic lateral scleros is (FALS). Results from several transgenic studies in which FALS-related SO D1 mutations have been expressed have suggested that mutant SOD1 proteins i nduce cytotoxicity through a toxic gain of function, although the specific mechanism of this has not been fully clarified. To investigate the mechanis m of toxicity induced by the mutant SOD1 associated with FALS, we generated transgenic Caenorhabditis elegans strains that contain wild-type and mutan t human A4V, G37R and G93A SOD1 recombinant plasmids. The transgenic strain s expressing mutant human SOD1 showed greater vulnerability to oxidative st ress induced by 0.2 mM paraquat than a control that contained the wild-type human SOD1. In the absence of oxidative stress, mutant human SOD1 proteins were degraded more rapidly than the wild-type human SOD1 protein in C.eleg ans. In the presence of oxidative stress, however, this rapid degradation w as inhibited, and the transgenic C.elegans co-expressing mutant human SOD1 and green fluorescent proteins (GFPs) in muscle tissues demonstrated discre te aggregates in the adult stage. These results suggest that oxidative dama ge inhibits the degradation of FALS-related mutant human SOD1 proteins, res ulting in an aberrant accumulation of mutant proteins that might contribute to the cytotoxicity.