{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T11:55:35Z","timestamp":1764244535500,"version":"3.46.0"},"reference-count":77,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n\/FEDER","doi-asserted-by":"publisher","award":["PID2021-122785OB-I00"],"award-info":[{"award-number":["PID2021-122785OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Marat\u00f3 de TV3 Foundation","award":["202005-30"],"award-info":[{"award-number":["202005-30"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuregulins (NRGs) are ligands of tyrosine kinase receptors from the ErbB family and play multiple developmental roles. NRG1\u2013ErbB signaling regulates myelination and has been associated with amyotrophic lateral sclerosis (ALS) pathology. Given the potential therapeutic relevance of this pathway for motor neuron (MN) diseases, we employed a transgenic (TG) mouse with persistent neuronal overexpression of neuregulin type III (NRG1-III) to investigate its impact on the neuromuscular system. We performed an analysis of phenotypic changes in this TG model, including motor behavior, neuropathological evaluation by immunocytochemistry and ultrastructural examination of the spinal cord, peripheral nerves, and neuromuscular junctions (NMJs). Calcium dynamics in cultured MNs were also examined. We found that cholinergic C-boutons on TG MNs, where NRG1-III typically accumulates, exhibited upregulation of C-bouton-associated proteins and expansion of the subsynaptic cistern (SSC)-associated endoplasmic reticulum. Calcium imaging revealed altered homeostasis in TG MNs, accompanied by the upregulation of molecules linked to axonal plasticity. At NMJs, regressive changes involving autophagic dysregulation were observed. These alterations were accompanied by increased motor activity in behavioral tests. Overall, our findings indicate that persistently elevated NRG1-III signaling compromises MN connectivity and long-term health, a factor to consider when developing therapeutic strategies for neurodegenerative diseases such as ALS.<\/jats:p>","DOI":"10.3390\/ijms262311421","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:04:57Z","timestamp":1764151497000},"page":"11421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Overexpression of Neuronal NRG1-III in Mice Causes Long-Term Detrimental Changes in Lower Motor Neurons, Neuromuscular Synapses and Motor Behaviour"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4250-6689","authenticated-orcid":false,"given":"Sara","family":"Salvany","sequence":"first","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6451-724X","authenticated-orcid":false,"given":"Sara","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8563-3460","authenticated-orcid":false,"given":"Anna","family":"Casanovas","sequence":"additional","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5172-379X","authenticated-orcid":false,"given":"S\u00edlvia","family":"Gras","sequence":"additional","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-7447","authenticated-orcid":false,"given":"L\u00eddia","family":"Piedrafita","sequence":"additional","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5374-8755","authenticated-orcid":false,"given":"Mar","family":"Bosch-Queralt","sequence":"additional","affiliation":[{"name":"Paul-Flechsig Institute for Brain Research, Medical Faculty, University Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2477-2892","authenticated-orcid":false,"given":"Markus H.","family":"Schwab","sequence":"additional","affiliation":[{"name":"Paul-Flechsig Institute for Brain Research, Medical Faculty, University Leipzig, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1972-0115","authenticated-orcid":false,"given":"Jordi","family":"Calder\u00f3","sequence":"additional","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1413-2103","authenticated-orcid":false,"given":"Josep E.","family":"Esquerda","sequence":"additional","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7741-3223","authenticated-orcid":false,"given":"Olga","family":"Tarabal","sequence":"additional","affiliation":[{"name":"Grup de Patologia Neuromuscular Experimental, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Spain"},{"name":"Institut de Recerca Biom\u00e8dica de Lleida\u2014Fundaci\u00f3 Dr. Pifarr\u00e9, IRBLleida, 25198 Lleida, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0959-4388(00)00210-5","article-title":"Neuregulin and ErbB Receptor Signaling Pathways in the Nervous System","volume":"11","author":"Buonanno","year":"2001","journal-title":"Curr. 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