Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1

Abstract

Mutation in superoxide dismutase-1 (SOD1) causes the inherited degenerative neurological disease familial amyotrophic lateral sclerosis (ALS), a non-cell-autonomous disease: mutant SOD1 synthesis in motor neurons and microglia drives disease onset and progression, respectively. In this issue of the JCI, Harraz and colleagues demonstrate that SOD1 mutants expressed in human cell lines directly stimulate NADPH oxidase (Nox) by binding to Rac1, resulting in overproduction of damaging ROS (see the related article beginning on page 659). Diminishing ROS by treatment with the microglial Nox inhibitor apocynin or by elimination of Nox extends survival in ALS mice, reviving the proposal that ROS mediate ALS pathogenesis, but with a new twist: it's ROS produced by microglia.

Figure 1. Production of ROS by microglial Nox2 during inflammation is amplified by mutant SOD1 binding to Rac1 in ALS.

(A) Under normal conditions, cytosolic activators p67^phox, p47^phox, and p40^phox of the microglial Nox catalytic subunit Nox2 are not bound to Nox2, and Rac1 is linked to GDP. (B) Upon microglial activation, including following a stimulus generated from degenerating neurons, Nox is activated and the p47^phox subunit becomes phosphorylated and translocates the p67^phox/p47^phox/p40^phox complex to the membrane. The new report in this issue from Harraz and colleagues (20) shows that SOD1 stabilizes the Nox2 activator Rac1-GTP. The activated Nox complex produces O₂^•– and ROS derived from O₂^•–, which can in turn damage neurons. (C) In the case of mutant SOD1–induced ALS, Harraz and colleagues show that mutant SOD1 keeps Rac1 in its active GTP-bound form and increases the production of ROS by microglial cells. The drug apocynin blocks microglial production of ROS by inhibiting Nox2 and could potentially block other forms of Nox in additional cell types, including neurons and astrocytes.