Journal article
SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model
The Journal of clinical investigation, Vol.118(2), pp.659-670
02/01/2008
DOI: 10.1172/JCI34060
PMCID: PMC2213375
PMID: 18219391
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 (O
2
•–
) to H
2
O
2
. Here we demonstrate that SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase–dependent (Nox-dependent) O
2
•–
production by binding Rac1 and inhibiting its GTPase activity. Oxidation of Rac1 by H
2
O
2
uncoupled SOD1 binding in a reversible fashion, producing a self-regulating redox sensor for Nox-derived O
2
•–
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.
Details
- Title: Subtitle
- SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model
- Creators
- Maged M Harraz - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAJennifer J Marden - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAWeihong Zhou - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAYulong Zhang - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAAislinn Williams - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAVictor S Sharov - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAKathryn Nelson - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAMeihui Luo - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAHenry Paulson - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAChristian Schöneich - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAJohn F Engelhardt - Center for Gene Therapy, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.118(2), pp.659-670
- DOI
- 10.1172/JCI34060
- PMID
- 18219391
- PMCID
- PMC2213375
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 02/01/2008
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Psychiatry; Anatomy and Cell Biology; Iowa Neuroscience Institute; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984003439502771
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