Decreased glutathione levels cause overt motor neuron degeneration in hSOD1WT over-expressing mice

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. Several lines of evidence have shown that SOD1 mutations cause ALS through a gain of a toxic function that remains to be fully characterized. A significant share of our understanding of the mechanisms underlying the neurodegenerative process in ALS comes from the study of rodents over-expressing ALS-linked mutant hSOD1. These mutant hSOD1 models develop an ALS-like phenotype. On the other hand, hemizygous mice over-expressing wild-type hSOD1 at moderate levels (hSOD1(WT), originally described as line N1029) do not develop paralysis or shortened life-span. To investigate if a decrease in antioxidant defenses could lead to the development of an MS-like phenotype in hSOD1(WT) mice, we used knockout mice for the glutamate-cysteine ligase modifier subunit [GCLM(-/-)]. GCLM(-/-) mice are viable and fertile but display a 70-80% reduction in total glutathione levels. GCLM(-/-)/hSOD1(WT) mice developed overt motor symptoms (e.g. tremor, loss of extension ieflex in hind-limbs, decreased grip strength and paralysis) characteristic of mice models over-expressing ALS-linked mutant hSOD1. In addition, GCLM (-/-)/hSOD1(WT) animals displayed shortened life span. An accelerated decrease in the number of large neurons in the ventral horn of the spinal cord and degeneration of spinal root axons was observed in symptomatic GCLM (-/-)/hSOD1(WT) mice when compared to age-matched GCLM(+/+ )/hSOD1(WT) mice. Our results show that under conditions of chronic decrease in glutathione, moderate over-expression of wild-type SOD1 leads to overt motor neuron degeneration, which is similar to that induced by MS-linked mutant hSOD1 over-expression.