{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:01:56Z","timestamp":1780452116627,"version":"3.54.1"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Committee for Ataxic disease","award":["JP24K18681"],"award-info":[{"award-number":["JP24K18681"]}]},{"name":"Research Committee for Ataxic disease","award":["JP21K07456"],"award-info":[{"award-number":["JP21K07456"]}]},{"name":"Ministry of Health, Labor and Welfare, Japan","award":["JP24K18681"],"award-info":[{"award-number":["JP24K18681"]}]},{"name":"Ministry of Health, Labor and Welfare, Japan","award":["JP21K07456"],"award-info":[{"award-number":["JP21K07456"]}]},{"name":"JSPS KAKENHI","award":["JP24K18681"],"award-info":[{"award-number":["JP24K18681"]}]},{"name":"JSPS KAKENHI","award":["JP21K07456"],"award-info":[{"award-number":["JP21K07456"]}]},{"name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","award":["JP24K18681"],"award-info":[{"award-number":["JP24K18681"]}]},{"name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","award":["JP21K07456"],"award-info":[{"award-number":["JP21K07456"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spastic paraplegia 80 (SPG80), caused by mutations in ubiquitin-associated protein 1 (UBAP1), is a pure form of juvenile-onset hereditary spastic paraplegia (HSP) and leads to progressive motor dysfunction. Despite recent advances in the molecular analyses of HSP, disease-modifying therapy has not been established for HSP including SPG80. In the present study, we evaluated the therapeutic potential of 4-phenylbutyric acid (4-PBA), a chemical chaperone and histone deacetylase inhibitor, in Ubap1 knock-in (KI) mice expressing a disease-associated truncated UBAP1 variant. We found that 4-PBA administration significantly improved the motor performance of KI mice in the rotarod and beam walk tests, with maximal benefits achieved when given during pre- or early-symptomatic stages. Partial efficacy was also observed when treatment began after symptom onset in KI mice. Furthermore, 4-PBA attenuated spinal microglial activation and partially restored microglial morphology, although astrocytic reactivity remained unchanged. These findings support 4-PBA as a candidate therapeutic compound for SPG80 and highlight the potential of proteostasis-targeted interventions in HSPs.<\/jats:p>","DOI":"10.3390\/ijms26199779","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T08:22:08Z","timestamp":1759911728000},"page":"9779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["4-Phenylbutyric Acid Improves Gait Ability of UBAP1-Related Spastic Paraplegia Mouse Model: Therapeutic Potential for SPG80"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6443-360X","authenticated-orcid":false,"given":"Keisuke","family":"Shimozono","sequence":"first","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1482-7319","authenticated-orcid":false,"given":"Yeon-Jeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1185-5464","authenticated-orcid":false,"given":"Haitian","family":"Nan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kozo","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunori","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8617-3695","authenticated-orcid":false,"given":"Yuji","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fujio","family":"Isono","sequence":"additional","affiliation":[{"name":"Centre for Advancing Clinical Research (CACR), Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3766-8744","authenticated-orcid":false,"given":"Masaru","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Organization for the Promotion of Research and Social Collaboration, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6184-3106","authenticated-orcid":false,"given":"Schuichi","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1566-1325","authenticated-orcid":false,"given":"Toshihisa","family":"Ohtsuka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5400-7107","authenticated-orcid":false,"given":"Yoshihisa","family":"Takiyama","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan"},{"name":"Department of Neurology, Fuefuki Central Hospital, Yamanashi 406-0032, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s11910-996-0011-1","article-title":"Hereditary spastic paraplegia","volume":"6","author":"Fink","year":"2006","journal-title":"Curr. 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