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While central nervous system (CNS) pathology is well documented, the impact on peripheral tissues remains unclear. Having previously described severe spinal cord pathology, we investigated whether PPT1 deficiency also impacts the neuromuscular junction (NMJ) and skeletal muscle, and whether early systemic gene therapy can prevent these disease manifestations. NMJ morphology, terminal Schwann cell (tSC) coverage, and skeletal muscle structure were examined in symptomatic and end-stage Ppt1\u2212\/\u2212 mice. Neonatal mice received systemic AAV9-hCLN1 gene therapy via intravenous injection. Untreated Ppt1\u2212\/\u2212 mice exhibited pronounced NMJ pathology, including progressive tSC loss, apparently reduced innervation, and increased abnormal acetylcholine receptor clustering. In parallel, we observed skeletal muscle atrophy, with decreased myofiber diameter and reduced myonuclear content, despite preserved sciatic nerve morphology. Systemic AAV9-hCLN1 therapy partially prevented or ameliorated these phenotypes, preserving NMJ innervation and muscle fiber structure. These findings identify peripheral NMJ and muscle abnormalities as previously unrecognized features of CLN1 disease and provide proof-of-concept that early systemic gene therapy can mitigate these effects. Our results highlight the systemic nature of CLN1 pathology and support the need for treatments that address both CNS and peripheral targets for comprehensive disease modification.<\/jats:p>","DOI":"10.3390\/ijms27073080","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T08:22:36Z","timestamp":1774858956000},"page":"3080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic AAV9 Gene Therapy Mitigates Neuromuscular Junction Degeneration and Muscle Atrophy in a Mouse Model of CLN1 Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-3133","authenticated-orcid":false,"given":"Ewa A.","family":"Zi\u00f3\u0142kowska","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8384-0117","authenticated-orcid":false,"given":"Albina","family":"Jablonka-Shariff","sequence":"additional","affiliation":[{"name":"Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5880-2574","authenticated-orcid":false,"given":"Letitia L.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Eultgen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8132-6827","authenticated-orcid":false,"given":"Matthew D.","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4038-0338","authenticated-orcid":false,"given":"Daniel A.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5559-0832","authenticated-orcid":false,"given":"Mark S.","family":"Sands","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9882-4213","authenticated-orcid":false,"given":"Alison K.","family":"Snyder-Warwick","sequence":"additional","affiliation":[{"name":"Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1339-4750","authenticated-orcid":false,"given":"Jonathan D.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0022-510X(73)90075-0","article-title":"Infantile type of so-called neuronal ceroid-lipofuscinosis","volume":"18","author":"Santavuori","year":"1973","journal-title":"J. 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