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Redox modifier genes in amyotrophic lateral sclerosis in mice
Journal article   Open access   Peer reviewed

Redox modifier genes in amyotrophic lateral sclerosis in mice

Jennifer J Marden, Maged M Harraz, Aislinn J Williams, Kathryn Nelson, Meihui Luo, Henry Paulson and John F Engelhardt
The Journal of clinical investigation, Vol.117(10), pp.2913-2919
10/01/2007
DOI: 10.1172/JCI31265
PMCID: PMC1974865
PMID: 17853944
url
https://doi.org/10.1172/JCI31265View
Published (Version of record) Open Access

Abstract

Amyotrophic lateral sclerosis (ALS), one of the most common adult-onset neurodegenerative diseases, has no known cure. Enhanced redox stress and inflammation have been associated with the pathoprogression of ALS through a poorly defined mechanism. Here we determined that dysregulated redox stress in ALS mice caused by NADPH oxidases Nox1 and Nox2 significantly influenced the progression of motor neuron disease caused by mutant SOD1 G93A expression. Deletion of either Nox gene significantly slowed disease progression and improved survival. However, 50% survival rates were enhanced significantly more by Nox2 deletion than by Nox1 deletion. Interestingly, female ALS mice containing only 1 active X-linked Nox1 or Nox2 gene also had significantly delayed disease onset, but showed normal disease progression rates. Nox activity in spinal cords from Nox2 heterozygous female ALS mice was approximately 50% that of WT female ALS mice, suggesting that random X-inactivation was not influenced by Nox2 gene deletion. Hence, chimerism with respect to Nox-expressing cells in the spinal cord significantly delayed onset of motor neuron disease in ALS. These studies define what we believe to be new modifier gene targets for treatment of ALS.

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