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Updated: Jul 15, 2026
Lumbar Intrathecal Injection of SOD1-ASOs for Precise CNS Targeting and Predictive Efficacy in Human SOD1-G93A ALS Mice
Published on: February 24, 2026
Early decrease of mitochondrial DNA repair enzymes in spinal motor neurons of presymptomatic transgenic mice carrying
Tetsuro Murakami1, Makiko Nagai, Kazunori Miyazaki
1Department of Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. neuron@cc.okayama-u.ac.jp
Abstract:
Growing evidence has recently shown that mutant SOD1 accumulate in the mitochondria and cause vacuolation in transgenic mice carrying mutant SOD1, an animal model of amyotrophic lateral sclerosis (ALS). In this study, the expressions of DNA repair enzymes, oxoguanine glycosylase 1 (ogg1), DNA polymerase beta (polbeta), and DNA polymerase gamma (polgamma) were examined in transgenic mice with an ALS-linked mutant SOD1 gene, a valuable model for human ALS. In presymptomatic Tg mice, the nuclear form of ogg1 was upregulated, whereas mitochondrial ogg1 remained at the same level. DNA polymerase was selectively downregulated in the mitochondria. This study suggests an impaired protective mechanism against oxidative stress in mitochondria. The expressions of these enzymes are predominant in spinal motor neurons, suggesting a mechanism of selective motor neuron death in this animal model of ALS.
Insights
Mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) involves altered DNA repair. This study found impaired mitochondrial DNA repair enzymes in presymptomatic SOD1 mutant mice, suggesting a mechanism for motor neuron death in ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutant SOD1 accumulation in mitochondria is implicated in amyotrophic lateral sclerosis (ALS).
- Transgenic mice with mutant SOD1 serve as a valuable model for studying human ALS pathogenesis.
- Oxidative stress and DNA damage are key factors in neurodegenerative diseases.
Purpose of the Study:
- To investigate the expression of key DNA repair enzymes in the mitochondria of presymptomatic SOD1 mutant mice.
- To determine if mitochondrial DNA repair mechanisms are impaired in an animal model of ALS.
- To explore the potential link between altered DNA repair and selective motor neuron vulnerability in ALS.
Main Methods:
- Quantitative analysis of DNA repair enzyme expression (oxoguanine glycosylase 1, DNA polymerase beta, DNA polymerase gamma) in transgenic mice carrying a mutant SOD1 gene.
- Distinguishing between nuclear and mitochondrial localization of enzymes.
- Comparison of enzyme expression in presymptomatic transgenic mice versus controls.
Main Results:
- Upregulation of nuclear oxoguanine glycosylase 1 (ogg1) in presymptomatic transgenic mice.
- No significant change in mitochondrial ogg1 levels.
- Selective downregulation of mitochondrial DNA polymerases (polbeta and polgamma).
- These alterations suggest impaired mitochondrial DNA repair capacity.
Conclusions:
- Presymptomatic SOD1 mutant mice exhibit impaired mitochondrial DNA repair mechanisms.
- This impairment may contribute to oxidative stress and selective motor neuron death in ALS.
- Findings highlight mitochondrial dysfunction as a critical component of ALS pathogenesis.
