Motor neuron cell death in a mouse model of FALS is not mediated by the p53 cell survival regulator.

Mutant Cu/Zn superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis (FALS) causes selective motor neuron loss through unknown mechanisms of cell damage. Damaged neurons frequently undergo apoptosis mediated by the p53 cell survival regulator. We therefore studied whether motor neuron disease (MND) in mice expressing the human SOD1 mutant G93A is dependent on p53 by crossing G93A mice with p53-knockout mice. Since p53-/- mice's life expectance is usually shorter (160+/-49 days, n=11) than the time at which the G93A mice die from MND (212+/-50 days, n=7), only a few of the G93A/p53-/- double transgenics were expected to live to experience MND. Nevertheless, four of the 22 G93A/p53-/- mice succumbed to MND after 160+/-28 days, as expected under these conditions of competing death risks if the absence of p53 fails to protect from MND. Thus, MND in mice expressing G93A does not require p53. This conclusion is supported by histology: pre-symptomatic G93A mice display disease-associated vacuoles within the dendrites of motor neurons regardless of p53 status.