Spinal motor neuron loss occurs through a p53-and-p21-independent mechanism in the Smn mouse model of spinal muscular atrophy

Dec 31, 2020Experimental neurology

Spinal motor neuron loss happens without p53 or p21 involvement in a mouse model of spinal muscular atrophy

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Abstract

p53 and p21 depletion did not alter the timing or degree of spinal motor neuron loss in a milder SMA mouse model.

Spinal muscular atrophy (SMA) is linked to the loss of motor neurons and muscle atrophy due to a deficiency in the SMN protein.
Transcriptomic studies show consistent activation of the p53 pathway in SMA mouse models.
Previous research indicated that p53 induces spinal motor neuron loss in severe SMA models.
Increased levels of the protein p21, associated with cell cycle arrest and muscle atrophy, were observed in various SMA models.
Knockout of p53 reduced survival in SMA mice, while knockout of p21 extended their lifespan, indicating different roles for these proteins.
The findings suggest that p53 and p21 are not the main causes of motor neuron death in this milder SMA model.

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Spinal muscular atrophy (SMA) is a pediatric neuromuscular disease caused by genetic deficiency of the survival motor neuron (SMN) protein. Pathological hallmarks of SMA are spinal motor neuron loss and skeletal muscle atrophy. The molecular mechanisms that elicit and drive preferential motor neuron degeneration and death in SMA remain unclear. Transcriptomic studies consistently report p53 pathway activation in motor neurons and spinal cord tissue of SMA mice. Recent work has identified p53 as an inducer of spinal motor neuron loss in severe Δ7 SMA mice. Additionally, the cyclin-dependent kinase inhibitor P21 (Cdkn1a), an inducer of cell cycle arrest and mediator of skeletal muscle atrophy, is consistently increased in motor neurons, spinal cords, and other tissues of various SMA models. p21 is a p53 transcriptional target but can be independently induced by cellular stressors. To ascertain whether p53 and p21 signaling pathways mediate spinal motor neuron death in milder SMA mice, and how they affect the overall SMA phenotype, we introduced Trp53 and P21 null alleles onto the Smnbackground. We found that p53 and p21 depletion did not modulate the timing or degree of Smnmotor neuron loss as evaluated using electrophysiological and immunohistochemical methods. Moreover, we determined that Trp53 and P21 knockout differentially affected Smnmouse lifespan: p53 ablation impaired survival while p21 ablation extended survival through Smn-independent mechanisms. These results demonstrate that p53 and p21 are not primary drivers of spinal motor neuron death in Smnmice, a milder SMA mouse model, as motor neuron loss is not alleviated by their ablation. 2B/-2B/-2B/-2B/-

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Spinal motor neuron loss occurs through a p53-and-p21-independent mechanism in the Smn mouse model of spinal muscular atrophy

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