Related Experiment Video
Updated: Jun 28, 2026
A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Progressive decrease in the level of YAPdeltaCs, prosurvival isoforms of YAP, in the spinal cord of transgenic mouse
Nobutoshi Morimoto1, Makiko Nagai, Kazunori Miyazaki
1Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University, 2-5-1 Shikata-cho, Okayama, Japan.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease caused by the selective death of motor neurons. Between 5% and 10% of ALS patients have a genetically inherited form of the disease known as familial ALS (FALS), and approximately 20% of FALS patients have mutations in the SOD1 gene. Although the mechanism underlying motor neuron death has not yet been fully clarified, it is supposed to be not completely consistent with apoptosis, necrosis, or autophagic cell death. Recently, it was found that general transcriptional repression induces slowly progressive atypical cell death associated with the shift of balance between YAPdeltaCs as prosurvival factors and activated p73 promoting apoptosis. This type of neuronal death was named transcriptional repression-induced atypical death (TRIAD). Therefore, to investigate possible relationships between the mechanism of motor neuron death in ALS and TRIAD, G93ASOD1 transgenic mice (Tg) were examined as an ALS model. The levels of YAPdeltaCs in the spinal cords of Tg mice decreased with disease progression, even during the presymptomatic stage, whereas FL-YAP, a p73 cofactor that promotes apoptosis, was preserved until the late symptomatic stage. Although the expression of total p73 also decreased with age in Tg mice, the ratio of phosphorylated p73 to total p73 increased during the late symptomatic stage in Tg mice. These results suggest that the progressive decrease in the levels of YAPdeltaCs and the relative increase in phosphorylation of p73 over the time course are correlated with disease progression in ALS model animals.
Insights
Amyotrophic lateral sclerosis (ALS) involves motor neuron death. This study links ALS progression in mouse models to a decrease in prosurvival YAPdeltaCs and an increase in pro-apoptotic p73, suggesting a novel cell death mechanism.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with unclear cell death mechanisms.
- Familial ALS (FALS) accounts for 5-10% of cases, with SOD1 mutations in ~20% of FALS patients.
- Existing cell death pathways like apoptosis and necrosis do not fully explain motor neuron demise in ALS.
Purpose of the Study:
- To investigate the potential link between motor neuron death in ALS and transcriptional repression-induced atypical death (TRIAD).
- To examine the roles of YAPdeltaCs and p73 in an established mouse model of ALS.
Main Methods:
- Utilized G93ASOD1 transgenic mice (Tg) as a model for familial ALS.
- Analyzed spinal cord tissue from Tg mice at various disease stages.
- Quantified levels of YAPdeltaCs, FL-YAP, total p73, and phosphorylated p73.
Main Results:
- YAPdeltaCs levels progressively decreased in Tg mice spinal cords with disease progression.
- FL-YAP levels remained stable until late symptomatic stages in Tg mice.
- While total p73 decreased with age, its phosphorylation ratio increased in late-stage symptomatic Tg mice.
Conclusions:
- The findings suggest that a shift in the balance between YAPdeltaCs and p73, specifically decreasing YAPdeltaCs and increasing p73 phosphorylation, correlates with ALS disease progression.
- This supports the hypothesis that TRIAD may contribute to motor neuron death in ALS.
- Further research into TRIAD could reveal new therapeutic targets for ALS.
