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Early decrease of survival factors and DNA repair enzyme in spinal motor neurons of presymptomatic transgenic mice
Isao Nagano1, Tetsuro Murakami, Yasuhiro Manabe
1Department of Neurology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan. inagano@cc.okayama-u.ac.jp
Abstract:
The primary pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS) have been elusive. Some of the mechanisms would be implicated in an imbalance between death and survival factors, and impairment of DNA repair possibly caused by oxidative stress. Phosphatidylinositol 3-kinase (PI3-K) and its downstream effector, Akt/protein kinase B (PKB), have been shown to play a pivotal role in neuronal survival against apoptosis supported by neurotrophic factors. To elucidate the mechanisms of motor neuron death in ALS, we examined the expression of PI3-K, Akt, and the DNA repair enzyme redox factor-1 (Ref-1) protein in the spinal cord of transgenic mice with an ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) gene, a valuable model for human ALS. Immunoblotting and immunocytochemical analyses showed that most spinal motor neurons lost immunoreactivity for PI3-K, Akt, and Ref-1 in the presymptomatic stage that preceded a significant loss of neurons. These results suggest that an early decrease of survival signal proteins and a DNA repair enzyme in the spinal motor neurons may account for the mutant SOD1-mediated motor neuron death in this animal model of ALS.
Insights
Amyotrophic lateral sclerosis (ALS) motor neuron death may stem from early losses in survival signaling proteins and DNA repair enzymes. This occurs in a mouse model before significant neuron loss, offering insights into ALS pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) pathogenesis remains unclear, with proposed mechanisms including imbalanced survival/death factors and impaired DNA repair due to oxidative stress.
- Phosphatidylinositol 3-kinase (PI3-K) and Akt/protein kinase B (PKB) are crucial for neuronal survival against apoptosis, often mediated by neurotrophic factors.
Purpose of the Study:
- To investigate the expression of PI3-K, Akt, and redox factor-1 (Ref-1) in the spinal cord of a transgenic mouse model of ALS.
- To elucidate the early molecular mechanisms underlying motor neuron death in ALS.
Main Methods:
- Utilized immunoblotting and immunocytochemical analyses.
- Examined spinal cord tissue from transgenic mice expressing an ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) gene.
Main Results:
- A significant loss of immunoreactivity for PI3-K, Akt, and Ref-1 was observed in spinal motor neurons during the presymptomatic stage.
- This decrease in survival signaling proteins and DNA repair enzyme occurred before substantial neuronal loss.
Conclusions:
- Early reduction in survival signal proteins (PI3-K, Akt) and the DNA repair enzyme (Ref-1) may drive motor neuron death in this ALS mouse model.
- These findings suggest potential therapeutic targets for intervening in early ALS progression.