Deleting redox modifier gene slows disease progression in ALS mouse model

Marden JJ et al. (2007) Redox modifier genes in amyotrophic lateral sclerosis in mice. J Clin Invest 117: 2913–2919

Although the exact mechanism of neurodegeneration in amyotrophic lateral sclerosis (ALS) is not known, redox stress has been associated with disease progression in mouse models of the disease. In a recent study, Marden et al. examined the effect of NADPH oxidase gene deletions on disease progression in transgenic mice overexpressing a mutant form of human superoxide dismutase 1 (SOD1^G93A) that is found in patients with ALS.

The investigators demonstrated that deletion of the NADPH oxidase genes Nox1 or Nox2 significantly extended the life span of hemizygous SOD1^G93A mice compared with control animals without Nox1 or Nox2 deletions, with the increase in 50% survival rate being markedly higher in Nox2 knockout mice. Compared with controls, Nox2 knockout also resulted in a significant decrease in spinal cord levels of NADPH-dependent superoxide production at the time of clinical death, and reduced the loss of motor neurons in the lumbar spinal cord. In female SOD1^G93A mice heterozygous for the X-linked Nox2 gene, levels of superoxide production in the spinal cord were intermediate between those of control and Nox2 knockout mice, affording these animals approximately half the life span gain of Nox2 knockout females.

A neuroprotective effect of reducing the activity of the Nox2 oxidase has been demonstrated in previous studies, but not to the degree seen here. Differences in genetic background of the mice studied might explain this discrepancy. Caution is needed when extrapolating the results to humans, but NADPH oxidase genes could prove to be a target for the treatment of ALS.