Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

The hallmark of spinal muscular atrophy (SMA), an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons. [Display omitted] •SMN deficiency induces early p53 activation in vulnerable SMA motor neurons•Inhibition of p53 prevents motor neuron degeneration in SMA mice•p53S18 phosphorylation selectively marks degenerating SMA motor neurons•Amino-terminal phosphorylation of p53 is required for motor neuron degeneration Ubiquitous SMN deficiency causes the death of specific motor neuron pools in SMA, but the mechanisms underlying this selectivity are unknown. Simon et al. identify nuclear accumulation and phosphorylation of p53 as distinct, converging mechanisms induced by SMN deficiency that trigger selective death of vulnerable SMA motor neurons.