Redox modifier genes in amyotrophic lateral sclerosis in mice

Jennifer J. Marden, Maged Harraz, Aislinn J. Williams, Kathryn Nelson, Meihui Luo, Henry Paulson, John F. Engelhardt

Research output: Contribution to journalArticle

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 SOD1G93A 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.

Original languageEnglish (US)
Pages (from-to)2913-2919
Number of pages7
JournalJournal of Clinical Investigation
Volume117
Issue number10
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

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Modifier Genes
Amyotrophic Lateral Sclerosis
Oxidation-Reduction
Disease Progression
Spinal Cord
X Chromosome Inactivation
Motor Neuron Disease
Chimerism
NADPH Oxidase
Gene Deletion
Neurodegenerative Diseases
Genes
Inflammation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Marden, J. J., Harraz, M., Williams, A. J., Nelson, K., Luo, M., Paulson, H., & Engelhardt, J. F. (2007). Redox modifier genes in amyotrophic lateral sclerosis in mice. Journal of Clinical Investigation, 117(10), 2913-2919. https://doi.org/10.1172/JCI31265

Redox modifier genes in amyotrophic lateral sclerosis in mice. / Marden, Jennifer J.; Harraz, Maged; Williams, Aislinn J.; Nelson, Kathryn; Luo, Meihui; Paulson, Henry; Engelhardt, John F.

In: Journal of Clinical Investigation, Vol. 117, No. 10, 01.10.2007, p. 2913-2919.

Research output: Contribution to journalArticle

Marden, JJ, Harraz, M, Williams, AJ, Nelson, K, Luo, M, Paulson, H & Engelhardt, JF 2007, 'Redox modifier genes in amyotrophic lateral sclerosis in mice', Journal of Clinical Investigation, vol. 117, no. 10, pp. 2913-2919. https://doi.org/10.1172/JCI31265
Marden JJ, Harraz M, Williams AJ, Nelson K, Luo M, Paulson H et al. Redox modifier genes in amyotrophic lateral sclerosis in mice. Journal of Clinical Investigation. 2007 Oct 1;117(10):2913-2919. https://doi.org/10.1172/JCI31265
Marden, Jennifer J. ; Harraz, Maged ; Williams, Aislinn J. ; Nelson, Kathryn ; Luo, Meihui ; Paulson, Henry ; Engelhardt, John F. / Redox modifier genes in amyotrophic lateral sclerosis in mice. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 10. pp. 2913-2919.
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