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

Redox modifier genes in amyotrophic lateral sclerosis in mice

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.

Authors

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

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Figure 3

Disease phenotyping of Nox2 genotypes on the SOD1G93A ALS background.

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Disease phenotyping of Nox2 genotypes on the SOD1G93A ALS background. ...
(A) Survival data of male and female mice for the given genotypes. Boxes denote mice treated for eye infections with antibiotics; those marked with an X denote mice that were unsuccessfully treated and died from eye infections. Circles denote mice that never contracted eye infection. Numbers denote mean survival in days. (B) Rotarod data demonstrating the mean latency time maintained on the rotarod for each given genotype as a function of age. Results are mean ± SEM for the same mice as in A. (C) Stride length data demonstrating the mean stride distance for each given genotype as a function of age. Results are mean ± SEM for the same mice as in A. (D) Mean stride lengths at 120 days for the indicated genotypes. Representative raw stride length data is shown at right.