{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T19:54:13Z","timestamp":1783367653742,"version":"3.54.6"},"reference-count":53,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004054","name":"King Abdulaziz University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011776","name":"MND Scotland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011776","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and \u2018dying\u2010back\u2019 pathology in models of SOD1\u2010dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP\u201043, a key mediator protein in ALS, is overexpressed in neurons in Thy1\u2010hTDP\u201043<jats:sup>WT<\/jats:sup> mice. We therefore aimed to comprehensively analyse NMJ pathology in this model of ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of TDP\u201043 was assessed via western blotting. Immunohistochemistry techniques, alongside NMJ\u2010morph quantification, were used to analyse motor neuron number, NMJ denervation status and terminal Schwann cell morphology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We present a time course of progressive, region\u2010specific motor neuron pathology in Thy1\u2010hTDP\u201043<jats:sup>WT<\/jats:sup> mice. Thy1\u2010driven hTDP\u201043 expression increased steadily, correlating with developing hindlimb motor weakness and associated motor neuron loss in the spinal cord with a median survival of 21\u2009days. Pronounced NMJ denervation was observed in hindlimb muscles, mild denervation in cranial muscles but no evidence of denervation in either forelimb or trunk muscles. NMJ pathology was restricted to motor nerve terminals, with denervation following the same time course as motor neuron loss. Terminal Schwann cells were lost from NMJs in hindlimb muscles, directly correlating with denervation status.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Thy1\u2010hTDP\u201043<jats:sup>WT<\/jats:sup> mice represent a severe model of ALS, with NMJ pathology\/denervation of distal muscles and motor neuron loss, as observed in ALS patients. This model therefore provides an ideal platform to investigate mechanisms of dying\u2010back pathology, as well as NMJ\u2010targeting disease\u2010modifying therapies in ALS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12925","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T08:42:28Z","timestamp":1689756148000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP\u201043 overexpression mouse model of amyotrophic lateral sclerosis"],"prefix":"10.1111","volume":"49","author":[{"given":"Abrar","family":"Alhindi","sequence":"first","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research  Edinburgh UK"},{"name":"Faculty of Medicine, Department of Anatomy King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Shand","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana S.","family":"Leite","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research  Edinburgh UK"},{"name":"School of Medicine UNESP\u2010S\u00e3o Paulo State University  Botucatu Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Ting","family":"Huang","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinja","family":"van der Hoorn","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zara","family":"Ridgway","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School: Biomedical Sciences University of Edinburgh  Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiterie M. 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