{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:48:00Z","timestamp":1792140480545,"version":"4.4.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007165","name":"University of Missouri","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["IS3-R2.23"],"award-info":[{"award-number":["IS3-R2.23"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["SG\/14-15\/08"],"award-info":[{"award-number":["SG\/14-15\/08"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["417757"],"award-info":[{"award-number":["417757"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Spinal muscular atrophy (SMA) is a childhood motor neuron disease caused by anomalies in the SMN1 gene. Although therapeutics have been approved for the treatment of SMA, there is a therapeutic time window, after which efficacy is reduced. Hallmarks of motor unit pathology in SMA include loss of motor-neurons and neuromuscular junction (NMJs). Following an increase in Smn levels, it is unclear how much damage can be repaired and the degree to which normal connections are re-established. Here, we perform a detailed analysis of motor unit pathology before and after restoration of Smn levels. Using a Smn-inducible mouse model of SMA, we show that genetic restoration of Smn results in a dramatic reduction in NMJ pathology, with restoration of innervation patterns, preservation of axon and endplate number and normalized expression of P53-associated transcripts. Notably, presynaptic swelling and elevated Pmaip levels remained. We analysed the effect of either early or delayed treated of an antisense oligonucleotide (ASO) targeting SMN2 on a range of differentially vulnerable muscles. Following ASO administration, the majority of endplates appeared fully occupied. However, there was an underlying loss of axons and endplates, which was more prevalent following a delay in treatment. There was an increase in average motor unit size following both early and delayed treatment. Together this work demonstrates the remarkably regenerative capacity of the motor neuron following Smn restoration, but highlights that recovery is incomplete. This work suggests that there is an opportunity to enhance neuromuscular junction recovery following administration of Smn-enhancing therapeutics.<\/jats:p>","DOI":"10.1093\/hmg\/ddac097","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T19:27:15Z","timestamp":1651001235000},"page":"3107-3119","source":"Crossref","is-referenced-by-count":18,"title":["Motor unit recovery following Smn restoration in mouse models of spinal muscular atrophy"],"prefix":"10.1093","volume":"31","author":[{"given":"Laura H","family":"Comley","sequence":"first","affiliation":[{"name":"Centre for Discovery Brain Sciences , University of Edinburgh, Edinburgh, EH8 9XD , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research , University of Edinburgh, Edinburgh, EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A","family":"Kline","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences , University of Edinburgh, Edinburgh, EH8 9XD , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research , University of Edinburgh, Edinburgh, EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison K","family":"Thomson","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences , University of Edinburgh, Edinburgh, EH8 9XD , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research , University of Edinburgh, Edinburgh, EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Woschitz","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences , University of Edinburgh, Edinburgh, EH8 9XD , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research , University of Edinburgh, Edinburgh, EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Villal\u00f3n","family":"Landeros","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center , University of Missouri, Columbia, MO 65211 , USA"},{"name":"Department of Biological Chemistry , Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erkan Y","family":"Osman","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center , University of Missouri, Columbia, MO 65211 , USA"},{"name":"Department of Veterinary Pathobiology , College of Veterinary Medicine, University of Missouri, Columbia, MO 65211 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian L","family":"Lorson","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center , University of Missouri, Columbia, MO 65211 , USA"},{"name":"Department of Veterinary Pathobiology , College of Veterinary Medicine, University of Missouri, Columbia, MO 65211 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6841-702X","authenticated-orcid":false,"given":"Lyndsay M","family":"Murray","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences , University of Edinburgh, Edinburgh, EH8 9XD , UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research , University of Edinburgh, Edinburgh, EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"2022091512051903800_ref1","article-title":"Spinal muscular atrophy: from rags to riches","volume-title":"Neuromuscul Disord","author":"","year":"2021"},{"key":"2022091512051903800_ref2","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s40263-018-0545-1","article-title":"Nusinersen: a review in 5q spinal muscular atrophy","volume":"32","author":"Hoy","year":"2018","journal-title":"CNS Drugs"},{"key":"2022091512051903800_ref3","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41434-019-0085-4","article-title":"AAV9 vector: a novel modality in gene therapy for spinal muscular atrophy","volume":"26","author":"Pattali","year":"2019","journal-title":"Gene Ther."},{"key":"2022091512051903800_ref4","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1007\/s40265-020-01410-z","article-title":"Risdiplam: first approval","volume":"80","author":"Dhillon","year":"2020","journal-title":"Drugs"},{"key":"2022091512051903800_ref5","doi-asserted-by":"crossref","first-page":"6501","DOI":"10.1021\/acs.jmedchem.8b00741","article-title":"Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA)","volume":"61","author":"Ratni","year":"2018","journal-title":"J. Med. Chem."},{"key":"2022091512051903800_ref6","doi-asserted-by":"crossref","first-page":"e2492","DOI":"10.1212\/WNL.0000000000007527","article-title":"Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1\/2 studies","volume":"92","author":"Darras","year":"2019","journal-title":"Neurology"},{"key":"2022091512051903800_ref7","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1007\/s12035-017-0831-9","article-title":"Time is motor neuron: therapeutic window and its correlation with pathogenetic mechanisms in spinal muscular atrophy","volume":"55","author":"Govoni","year":"2018","journal-title":"Mol. 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Comp. Neurol."},{"key":"2022091512051903800_ref16","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/hmg\/ddr453","article-title":"Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy","volume":"21","author":"Ling","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2022091512051903800_ref17","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1093\/hmg\/ddm367","article-title":"Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy","volume":"17","author":"Murray","year":"2008","journal-title":"Hum. Mol. 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