Redox modifier genes in amyotrophic lateral sclerosis in mice
Open accessAbstract
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 Noxexpressing 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. Results and Discussion Gene deletion of Nox1 or Nox2 increases survival and slows disease progression in SOD1 G93A transgenic mice.Given that enhanced redox stress has been associated with disease progression in ALS mouse models, we sought to evaluate 2 potential Nox genes responsible for ROS generation in hemizygous SOD1 G93A transgenic mice and their affect on the progression of motor neuron disease.We bred female Nox1-KO and Nox2-KO mice to hemizygous male SOD1 G93A ALS mice
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The cellular sources of Nox1 and the mechanisms by which Nox1 may promote neural tissue damage remained undetermined.
“but the cellular sources of Nox1 and the mechanisms by which Nox1 may promote neural tissue damages remained undetermined (Marden et al., 2007).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Marden et al., 2007
The Introduction reports that Nox1 deletion delayed motor-neuron disease in ALS mice, and the Conclusions (indexed under Figure 2; page unavailable) describe possible ways oxidase-derived ROS could contribute to neurodegeneration. Our copy does not identify Nox1’s cellular sources or explicitly state that its specific damage mechanisms remained undetermined; the proposed mechanisms concern ROS generally. (LLM, conf=0.72)
Experimental — accuracy not yet measuredNox1 deletion increases survival in a mouse model of amyotrophic lateral sclerosis.
“Nox1 deletion was reported to increase survival in a mouse model of amyotrophic lateral sclerosis (ALS)”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Marden et al., 2007
Invalidation of Nox1 retards progression in a mouse model of human ALS.
“whereas invalidation of Nox1 retards progression (Marden et al., 2007).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Marden et al., 2007
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- Authors
- Marden, J. J., Harraz, M. M., Williams, A. J., Nelson, K., Luo, M., Paulson, H., & Engelhardt, J. F.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Engelhardt, John F.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-10-01
- Volume
- 117
- Issue
- 10
- Pages
- 2913-2919
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1974865
- OpenAlex
- W2064132577
- Cited by
- 145
- References
- 4
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 10 · 2017: 11 · 2016: 2 · 2015: 6 · 2014: 16 · 2013: 8 · 2012: 7
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK54759)
- National Institute of General Medical Sciences (T32GM007337)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK067928, DK54759, R01DK067928, P30DK054759)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, redox stress, NADPH oxidase, NOX1, NOX2, SOD1 G93A mice, motor neuron disease, genetic modifiers, chimerism, reactive oxygen species, disease progression
- MeSH terms
- Superoxide Dismutase-1, NADPH Oxidase 1, NADPH Oxidase 2, Amyotrophic Lateral Sclerosis, Animals, Female, Humans, Male, Membrane Glycoproteins, NADH, NADPH Oxidoreductases, Oxidation-Reduction, Spinal Cord, Superoxide Dismutase, Gene Deletion, Mice, Knockout, Oxidative Stress, Disease Progression, NADPH Oxidases, Mice
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