Alteration of the Bcl-x/Bax ratio in a transgenic mouse model of amyotrophic lateral sclerosis: Evidence for the implication of the p53 signaling pathway

Molecular mechanisms promoting neuronal death in amyotrophic lateral sclero sis (ALS) were investigated using transgenic mice that overexpressed the G8 6R mutated form of the Cu/Zn superoxide dismutase (SOD1) gene. We observed: (i) alteration of the Bcl-x/Bax ratio and (ii) activation of the transcrip tion factor p53, as deduced from its location within neuron nuclei. We furt her demonstrated that ectopic expression of the G86R mutant SOD1 in PC12 ce lls enhanced both p53 expression and phosphorylation, leading to transcript ional stimulation of p53-responsive genes. These findings provide evidence that the p53 signaling pathway is activated in SOD1-linked familial ALS and may play a causative role in spinal cord neuron apoptosis by modulating th e Bcl-x/Bax ratio, (C) 2000 Academic Press.