{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:51:52Z","timestamp":1792036312346,"version":"4.4.0"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Telethon","doi-asserted-by":"publisher","award":["GGP20101"],"award-info":[{"award-number":["GGP20101"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health (\u201cRicerca Corrente\u201d)","award":["GGP20101"],"award-info":[{"award-number":["GGP20101"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions. In this study, we investigated any potential existing link between sphingolipid modulation and myelin structure by performing both ultrastructural and biochemical analyses. Our findings demonstrated that the treatment with the glycosphingolipid modulator THI preserved myelin thickness and the overall structure and reduced both area and diameter of pathologically giant axons in the striatum of HD mice. These ultrastructural findings were associated with restoration of different myelin marker protein, such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and 2\u2032, 3\u2032 Cyclic Nucleotide 3\u2032-Phosphodiesterase (CNP). Interestingly, the compound modulated the expression of glycosphingolipid biosynthetic enzymes and increased levels of GM1, whose elevation has been extensively reported to be associated with reduced toxicity of mutant Htt in different HD pre-clinical models. Our study further supports the evidence that the metabolism of glycosphingolipids may represent an effective therapeutic target for the disease.<\/jats:p>","DOI":"10.3390\/ijms24065956","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T07:09:31Z","timestamp":1679468971000},"page":"5956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Treatment with the Glycosphingolipid Modulator THI Rescues Myelin Integrity in the Striatum of R6\/2 HD Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Giuseppe","family":"Pepe","sequence":"first","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4734-8798","authenticated-orcid":false,"given":"Paola","family":"Lenzi","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Capocci","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Marracino","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Pizzati","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Scarselli","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Di Pardo","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-5084","authenticated-orcid":false,"given":"Francesco","family":"Fornai","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"},{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Maglione","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed, Via Dell\u2019elettronica, 86077 Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41582-020-0389-4","article-title":"Huntington Disease: New Insights into Molecular Pathogenesis and Therapeutic Opportunities","volume":"16","author":"Tabrizi","year":"2020","journal-title":"Nat. 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