Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1.
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.
Boillée
Séverine
S
Ludwig Institute for Cancer Research, Department of Medicine, and Department of Neuroscience, UCSD, La Jolla, California 92030, USA.
Cleveland
Don W
DW
D000098:Acetophenones / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D017628:Microglia / Q000201:enzymology* / Q000473:pathology; D009046:Motor Neurons / Q000201:enzymology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000098:Acetophenones; D004791:Enzyme Inhibitors; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D013481:Superoxides; C056165:acetovanillone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein