| Summary: | Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. To investigate the role of antioxidant defenses in ALS we used knockout mice for the glutamate-cysteine ligase modifier subunit (GCLM−/−), which have a 70–80% reduction in total glutathione. Although GCLM(−/−) mice are viable and fertile, the life span of GCLM(−/−)/hSOD1G93A mice decreased in 55% when compared to GCLM(+/+)/hSOD1G93A mice. Decreased life span in GCLM(−/−)/hSOD1G93A mice was associated to increased oxidative stress, aggravated mitochondrial pathology and increased association of hSOD1 with the mitochondria. Interestingly, when the GCLM(−/−) animals were mated with a different ALS-model which overexpress the experimental mutation hSOD1H46R/H48Q, no effect was observed in survival of GCLM(−/−)/hSOD1H46R/H48Q mice; and little or no mitochondrial pathology was observed. Since a specific disease modifier, such as glutathione deficiency, may affect only certain hSOD1 mutants, these findings contribute to our understanding of the potential difference in the molecular pathways by which different hSOD1 mutants generate disease.
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