{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T06:47:54Z","timestamp":1782456474471,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,25]]},"group-title":"Neuroscience","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","award":["NS102451"],"award-info":[{"award-number":["NS102451"]}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["NS114218"],"award-info":[{"award-number":["NS114218"]}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["NS116400"],"award-info":[{"award-number":["NS116400"]}]},{"name":"DFG Research Training Group","award":["GRK 3102"],"award-info":[{"award-number":["GRK 3102"]}]},{"name":"DFG","award":["19693-1"],"award-info":[{"award-number":["19693-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,25]]},"abstract":"<jats:p>Selective neuronal vulnerability is a hallmark of many neurodegenerative diseases, yet how ubiquitous genetic insults cause highly selective neuronal loss remains poorly understood. In spinal muscular atrophy (SMA), reduced SMN levels trigger degeneration of specific motor neuron pools. Although non-apoptotic, p53-mediated death pathways have been implicated, p53 is expressed in both vulnerable and resistant neurons, leaving the downstream determinants of selective vulnerability unresolved. Here, we identify a p53-\u0394Np73 signaling axis as a previously unrecognized execution pathway driving motor neuron degeneration. Using differential transcriptional profiling of SMA motor neurons following pharmacological modulation of p53 activity, we uncover p73 as a critical downstream mediator of neuronal death. Notably, SMN deficiency induces cell-autonomous, p53-dependent expression of the \u0394Np73 isoform selectively in vulnerable, but not resistant, motor neurons. \u0394Np73 induction precisely parallels the spatial and temporal pattern of degeneration in mouse models and is also detected in motor neurons from SMA patients. Strikingly, despite its established role as a pro-survival antagonist of p53, depletion of \u0394Np73 improves motor neuron survival and partially preserves neuromuscular junction integrity in SMA mice. These findings reveal a context-dependent, isoform-specific functional switch in p53 family signaling that redirects a canonical survival factor into a driver of neurodegeneration, identifying a novel molecular mechanism underlying selective neuronal vulnerability in SMA and a potential therapeutic target for neuroprotection.<\/jats:p>","DOI":"10.64898\/2026.06.20.733537","type":"posted-content","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T06:15:37Z","timestamp":1782454537000},"source":"Crossref","is-referenced-by-count":0,"title":["A p53-\u0394Np73 signaling axis drives selective motor neuron degeneration in spinal muscular atrophy"],"prefix":"10.64898","author":[{"given":"Maria J","family":"Carlini","sequence":"first","affiliation":[{"name":"Columbia University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Hu","sequence":"additional","affiliation":[{"name":"Columbia University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Sowoidnich","sequence":"additional","affiliation":[{"name":"Leipzig University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Yadav","sequence":"additional","affiliation":[{"name":"Columbia University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Garcia","sequence":"additional","affiliation":[{"name":"Columbia University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Savin","sequence":"additional","affiliation":[{"name":"Columbia University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte J","family":"Sumner","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilas","family":"Menon","sequence":"additional","affiliation":[{"name":"Columbia University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M","family":"Simon","sequence":"additional","affiliation":[{"name":"Leipzig University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9168-5628","authenticated-orcid":false,"given":"Livio","family":"Pellizzoni","sequence":"additional","affiliation":[{"name":"Columbia University;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.20.733537","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T06:15:37Z","timestamp":1782454537000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.20.733537"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.06.20.733537","relation":{},"subject":[],"published":{"date-parts":[[2026,6,25]]},"subtype":"preprint"}}