SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model
Maged M. Harraz, … , Christian Schöneich, John F. Engelhardt
Maged M. Harraz, … , Christian Schöneich, John F. Engelhardt
Published January 24, 2008
Citation Information: J Clin Invest. 2008;118(2):659-670. https://doi.org/10.1172/JCI34060.
View: Text | PDF
Research Article

SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model

Abstract

Neurodegeneration in familial amyotrophic lateral sclerosis (ALS) is associated with enhanced redox stress caused by dominant mutations in superoxide dismutase–1 (SOD1). SOD1 is a cytosolic enzyme that facilitates the conversion of superoxide (O2•–) to H2O2. Here we demonstrate that SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase–dependent (Nox-dependent) O2•– production by binding Rac1 and inhibiting its GTPase activity. Oxidation of Rac1 by H2O2 uncoupled SOD1 binding in a reversible fashion, producing a self-regulating redox sensor for Nox-derived O2•– production. This process of redox-sensitive uncoupling of SOD1 from Rac1 was defective in SOD1 ALS mutants, leading to enhanced Rac1/Nox activation in transgenic mouse tissues and cell lines expressing ALS SOD1 mutants. Glial cell toxicity associated with expression of SOD1 mutants in culture was significantly attenuated by treatment with the Nox inhibitor apocynin. Treatment of ALS mice with apocynin also significantly increased their average life span. This redox sensor mechanism may explain the gain-of-function seen with certain SOD1 mutations associated with ALS and defines new therapeutic targets.

Authors

Maged M. Harraz, Jennifer J. Marden, Weihong Zhou, Yulong Zhang, Aislinn Williams, Victor S. Sharov, Kathryn Nelson, Meihui Luo, Henry Paulson, Christian Schöneich, John F. Engelhardt

×

Figure 4

Treatment with the Nox inhibitor apocynin increases lifespan and slows disease progression in mice hemizygous for the SOD1G93A transgene.

Options: View larger image (or click on image) Download as PowerPoint
Treatment with the Nox inhibitor apocynin increases lifespan and slows d...
(A) Kaplan-Meier survival curve for mice treated with indicated doses of apocynin in their water beginning at 14 days of age. n is shown along with median survival time (arrowhead) for each group. Survival differences were significant in all between-group comparisons (log-rank test). (B) Age of disease onset, as determined by a 10% weight loss from peak body weight, for the various doses of apocynin. (C) Dose affect of apocynin treatment on survival index, measured as time from disease onset (as determined by weight loss) until clinical death. (D) Rate of NADPH-dependent O2•– production in total endomembranes isolated from lumbar spinal cords of end-stage SOD1G93Atransgenic mice (~120 days of age) that were either untreated or treated with apocynin (300 mg/kg) in the drinking water for 5 days prior to harvesting spinal cords (n = 5 per group). (E) DHE fluorescence was assessed in lumbar spinal cord sections from 2 mice evaluated in D. (F) Survival data of male and female mice at the indicated apocynin dose. Mice treated for eye infections with antibiotics are marked as squares; those unsuccessfully treated that died from eye infections are marked by “X” within the square. Circles denote animals that never contracted eye infection. n and mean survival time is indicated for each group. Data in B–D are mean ± SEM.