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Abstract: Spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of spinal motor neurons which leads to skeletal muscle atrophy. Proximal SMA results from the loss or mutation of the survival motor neuron (SMN) gene. In humans, the SMN gene is duplicated to produce two nearly identical genes, SMN1 and SMN2. SMN1 is lost in SMA but SMN2 is retained; in fact, the number of SMN2 copies correlates with disease severity. The SMN2 inducer D156844 increases the survival and improves phenotype of SMN∆7 SMA mice. Maternal diet also modifies the survival and phenotype of these mice. In this study, we show the effect of maternal diet on the protective effects of D156844 in SMN∆7 SMA mice. SMA mice maintained on the PicoLab20 Mouse diet survived longer when treated with D156844; the effect of diet was additive to the effect of D156844 on these mice. Brain levels of D156844 were higher in neonatal mice maintained on the PicoLab20 diet than those on the Harlan-Teklad 22/5 diet. SMN protein levels in the spinal cord were modestly elevated in D156844-treated, PicoLab20-maintained SMA mice. These data show that maternal diet does influence the responsiveness of D156844 in neonatal SMN∆7 SMA mice. [Copyright &y& Elsevier]

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 Smn 2B/− background. We found that p53 and p21 depletion did not modulate the timing or degree of Smn 2B/− motor neuron loss as evaluated using electrophysiological and immunohistochemical methods. Moreover, we determined that Trp53 and P21 knockout differentially affected Smn 2B/− mouse 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 Smn 2B/− mice, a milder SMA mouse model, as motor neuron loss is not alleviated by their ablation. • Cell stress-associated genes are upregulated in spinal cords of Smn 2B/− SMA mice. • Functional motor unit loss occurs at 14 days of age in C57BL/6 Smn 2B/− SMA mice. • Trp53 or P21 (Cdkn1a) genetic knockout does not rescue Smn 2B/− motor neuron loss. • Trp53 and P21 (Cdkn1a) ablation differentially impact survival of Smn 2B/− SMA mice. • p21 depletion does not attenuate skeletal muscle atrophy in Smn 2B/− SMA mice. [ABSTRACT FROM AUTHOR]