{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:11Z","timestamp":1792787591772,"version":"4.5.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences","award":["T32 GM007748"],"award-info":[{"award-number":["T32 GM007748"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"ELA","award":["2019-012I2"],"award-info":[{"award-number":["2019-012I2"]}]},{"name":"CDMRP","award":["HT94252310375"],"award-info":[{"award-number":["HT94252310375"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Avery project","award":["na"],"award-info":[{"award-number":["na"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Defective feedback inhibition of serine palmitoyltransferase (SPT) caused by pathogenic\n                    <jats:italic>SPTSSA<\/jats:italic>\n                    variants underlies childhood-onset complex hereditary spastic paraplegia, yet the developmental timing and therapeutic reversibility of sphingolipid dysregulation remain unclear. We generated a knock-in mouse carrying the disease-associated\n                    <jats:italic>SptssaT51I<\/jats:italic>\n                    variant and show that heterozygous animals exhibit preserved intrinsic SPT activity but impaired ORMDL-mediated regulation, leading to sustained elevation of bioactive sphingolipid intermediates that peak during postnatal myelination. Although gross myelin formation was initially maintained, excess sphingolipid flux rendered oligodendrocytes and neurons selectively vulnerable. Dietary L-serine, which augments SPT substrate availability, amplified sphingolipid accumulation in mutant but not wild-type mice, unmasking progressive spasticity, axonal injury, myelin ultrastructural defects, and, when administered during early postnatal development, severe pulmonary pathology likely responsible for lethality. Pharmacologic SPT inhibition with myriocin normalized sphingolipid synthesis, prevented serine-induced lethality, and reversed neurological and metabolic abnormalities. Translating these findings, treatment of a child with\n                    <jats:italic>SPTSSA-T51I<\/jats:italic>\n                    \u2013associated complex hereditary spastic paraplegia using the FDA approved SPT inhibitor D-Cycloserine resulted in sustained improvement in spasticity, reduced baclofen requirement, and decreased plasma levels of neurofilament light chain (NFL). These data define dysregulated sphingolipid biosynthesis as a developmentally and metabolically sensitive driver of neurodegeneration and suggest SPT inhibition as a mechanistically grounded therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.206228","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:00:16Z","timestamp":1790697616000},"source":"Crossref","is-referenced-by-count":0,"title":["Serine palmitoyltransferase (SPT) inhibition in SPTSSA-related complex hereditary spastic paraplegia"],"prefix":"10.1172","author":[{"given":"Yi","family":"Gong","sequence":"first","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Glover","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Gable","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sita D.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Golovanov","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Tassinari","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Casey","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Wishart","sequence":"additional","affiliation":[{"name":"Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise L.","family":"Townsend","sequence":"additional","affiliation":[{"name":"School of Health and Rehabilitation Sciences, MGH Institute of Health Professions, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Selig","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armen","family":"Yerevanian","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa M.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Eichler","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,29]]},"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/insight.jci.org\/articles\/view\/206228\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:00:17Z","timestamp":1790697617000},"score":1,"resource":{"primary":{"URL":"http:\/\/insight.jci.org\/articles\/view\/206228"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":0,"alternative-id":["10.1172\/jci.insight.206228"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.206228","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}