**3. Regulation of NADPH oxidase activity by mutant SOD1**

Several lines of evidence support the role of oxidative stress in mutant SOD1 toxicity, but some evidence suggest that interactions other than the redox properties of the enzyme stimulate oxidative stress by different mechanisms. Mutant SOD1 can induce oxidative stress by disruption of the redox-sensitive regulation of NADPH oxidase (Nox) in microglial cells. Noxs are transmembrane proteins that catalyze the reduction of oxygen to superoxide using NADPH as an electron donor (Brown and Griendling, 2009). Superoxide is then converted to hydrogen peroxide by SOD1. Under reducing conditions, SOD1 regulates Nox2 activation by binding and stabilizing Rac1. The oxidation of Rac1 by hydrogen peroxide disrupts the complex with SOD1 and inactivates Nox2. Upon expression of certain ALS SOD1 mutants, the dissociation of Rac1 from SOD1 is impaired and Nox2 remains active (Figure 1C). In addition, the expression of Nox2 is upregulated in the SOD1G93A mouse model and in ALS patients. In fact, gene deletion of Nox1 or Nox2 provides the larger protection to date in animal models of ALS (Harraz et al., 2008; Marden et al., 2007).
