{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:49:20Z","timestamp":1788544160348,"version":"build-2803163510"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T00:00:00Z","timestamp":1673827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["JP19bm0804001"],"award-info":[{"award-number":["JP19bm0804001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Core Center for iPS Cell Research of Research Center Network","award":["JP21bm0104001"],"award-info":[{"award-number":["JP21bm0104001"]}]},{"name":"JSPS KAKENHI","award":["JP 21K15863"],"award-info":[{"award-number":["JP 21K15863"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Membrane fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. During neurotransmitter exocytosis, SNARE proteins on a synaptic vesicle and the target membrane form a complex, resulting in neurotransmitter release. N-ethylmaleimide-sensitive factor (NSF), a homohexameric ATPase, disassembles the complex, allowing individual SNARE proteins to be recycled. Recently, the association between pathogenic NSF variants and developmental and epileptic encephalopathy (DEE) was reported; however, the molecular pathomechanism of NSF-related DEE remains unclear. Here, three patients with de novo heterozygous NSF variants were presented, of which two were associated with DEE and one with a very mild phenotype. One of the DEE patients also had hypocalcemia from parathyroid hormone deficiency and neuromuscular junction impairment. Using PC12 cells, a neurosecretion model, we show that NSF with DEE-associated variants impaired the recycling of vesicular membrane proteins and vesicle enlargement in response to exocytotic stimulation. In addition, DEE-associated variants caused neurodegenerative change and defective autophagy through overactivation of the mammalian\/mechanistic target of rapamycin (mTOR) pathway. Treatment with rapamycin, an mTOR inhibitor or overexpression of wild-type NSF ameliorated these phenotypes. Furthermore, neurons differentiated from patient-derived induced pluripotent stem cells showed neurite degeneration, which was also alleviated by rapamycin treatment or gene correction using genome editing. Protein structure analysis of NSF revealed that DEE-associated variants might disrupt the transmission of the conformational change of NSF monomers and consequently halt the rotation of ATP hydrolysis, indicating a dominant negative mechanism. In conclusion, this study elucidates the pathomechanism underlying NSF-related DEE and identifies a potential therapeutic approach.<\/jats:p>","DOI":"10.1093\/hmg\/ddad008","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T12:48:20Z","timestamp":1673873300000},"page":"1683-1697","source":"Crossref","is-referenced-by-count":10,"title":["Involvement of mTOR pathway in neurodegeneration in NSF-related developmental and epileptic encephalopathy"],"prefix":"10.1093","volume":"32","author":[{"given":"Takahiro","family":"Hayashi","sequence":"first","affiliation":[{"name":"Kyoto University Graduate School of Medicine Department of Pediatrics, , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Yano","sequence":"additional","affiliation":[{"name":"Kyoto University Graduate School of Medicine Department of Pediatrics, , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Kora","sequence":"additional","affiliation":[{"name":"Kyoto University Graduate School of Medicine Department of Pediatrics, , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Kyoto University Graduate School of Medicine Department of Pediatrics, , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Maizuru","sequence":"additional","affiliation":[{"name":"Kyoto University Graduate School of Medicine Department of Pediatrics, , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisei","family":"Kayaki","sequence":"additional","affiliation":[{"name":"Kyoto University Graduate School of Medicine Department of Pediatrics, , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinuko","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Kyoto University Graduate School of Medicine Department of Pediatrics, , Kyoto 606-8507 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsujiro","family":"Osawa","sequence":"additional","affiliation":[{"name":"Thyas Co. 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