ALS predisposition modifiers: Knock NOX, who's there? SOD1 mice still are

Abstract

The discovery that Zn/Cu superoxide dismutase (SOD1) gene mutations are responsible for 15–20% of familial forms of amyotrophic lateral sclerosis (ALS)1 led to extensive studies of the susceptibility of the motor neuron to oxidative stress. The role of the normal SOD1 function—the conversion of toxic superoxide into less damaging hydrogen peroxide—in ALS pathogenesis remains unclear. It is, however, known that the restricted expression of mutant SOD1 in either motor neurons, microglia or astrocytes has repeatedly been demonstrated to be insufficient for an effective triggering of ALS symptoms.2 Microglia, in particular, have the capacity to recognize a stressed neuron and either attempt to restore the function (immune response) or release toxic factors to prune the compromised neurons. In the case of ALS, this is particularly damaging because the neurons already have difficulty coping with superoxide radicals, which wildtype SOD1 would typically reduce and remove. It was observed that one of the redox-related genes, which is specifically upregulated in activated microglia in spinal cords responding in ALS, is NOX2.3 The NADPH oxidase (NOX) enzymes operate by generating reactive oxygen species in a coordinated manner, often in response to inflammatory signals or microorganisms (Figure 1). Thus, by knocking out NOX2 or other redox-related genes, it could be predicted that motor neurons would have less damaging and fewer insults from activated microglia. In an article by Marden et al4, a hemizygous mouse that harbors a G93A SOD1 mutation was crossed with a mouse null for the NOX1 or the NOX2 genes. This result had a dramatic effect on the lifespan, in particular of NOX2-null mutant SOD1 mice, which survived on average 229 days compared with 132 days for the mice only with a G93A point mutation. This increase of almost 100 days is one of the largest effects observed for SOD1 mutant mice; most manipulations influence lifespan by at most 10–20 days. The exact nature of this benefit is not fully understood and should be the source of compelling future research.