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Clinically, most SPG4 patients present with a pure phenotype marked by progressive spasticity in the lower extremities. It has also been reported that complex cases exhibit demyelination and cognitive deficits. Additionally, some\n                    <jats:italic>SPAST<\/jats:italic>\n                    variants have been determined in patients with multiple sclerosis (MS), indicating potential shared pathological mechanisms. Spastin is known to promote axonal regeneration by remodeling microtubules, whereas mutant Spastin disrupts microtubule dynamics and causes axonal transport defects in SPG4. However, whether Spastin dysfunction impairs regenerative processes such as myelination remains unknown. In this study, we investigated whether the SPG4\u2010associated\n                    <jats:italic>SPAST<\/jats:italic>\n                    mutations affect axonal myelination. Using an in\u00a0vitro cortical neuron\u2010oligodendrocyte co\u2010culture model, we found that pathogenic\n                    <jats:italic>SPAST<\/jats:italic>\n                    mutations result in a significant reduction in the myelination index. Furthermore, a cuprizone\u2010induced demyelination mouse model revealed a decrease in Spastin protein levels in demyelinated white matter. Given Spastin's role in axonal regeneration, we hypothesized that Spastin may also protect against demyelination. Supporting this, wild\u2010type Spastin expression protected neurons from demyelination in a cuprizone\u2010induced cell culture demyelination model. Together, these results suggest a role for Spastin in axonal myelination, and its dysfunction may compromise myelin stability. Our findings highlight that impaired myelin stability may represent a secondary pathological feature of SPG4, contributing to disease complexity. This dual role of Spastin in axonal maintenance and myelin stability suggests its potential relevance for contributing to complex forms of SPG4.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70407-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70407","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:02:26Z","timestamp":1773032546000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spastin Is Required to Prevent\n                    <i>SPAST<\/i>\n                    \u2010Related Demyelination"],"prefix":"10.1111","volume":"170","author":[{"given":"\u015eeyma","family":"Akarsu","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics Istanbul Technical University  Istanbul T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Didem M\u00fcge","family":"Orhan","sequence":"additional","affiliation":[{"name":"Department of Medical Biology Bah\u00e7e\u015fehir University School of Medicine  Istanbul T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timu\u00e7in","family":"Av\u015far","sequence":"additional","affiliation":[{"name":"Department of Medical Biology Bah\u00e7e\u015fehir University School of Medicine  Istanbul 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