Progressive decrease in the level of YAPdeltaCs, prosurvival isoforms of YAP, in the spinal cord of transgenic mouse carrying a mutant SOD1 gene

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 YAP-deltaCs and the relative increase in phosphorylation of p73 over the time course are correlated with disease progression in ALS model animals.