{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T16:09:52Z","timestamp":1784304592548,"version":"3.55.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K07855"],"award-info":[{"award-number":["21K07855"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for \u03b1-Synuclein (\u03b1Syn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown \u03b1Syn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on \u03b1Syn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in \u03b1Syn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble \u03b1Syn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates \u03b1Syn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing \u03b1Syn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble \u03b1Syn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates \u03b1Syn-induced neurotoxicity by altering the \u03b1Syn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of \u03b1-synucleinopathies.<\/jats:p>","DOI":"10.1093\/hmg\/ddae073","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T23:00:10Z","timestamp":1714604410000},"page":"1328-1338","source":"Crossref","is-referenced-by-count":8,"title":["\u03b1-Synuclein pathology in <i>Drosophila melanogaster<\/i> is exacerbated by haploinsufficiency of <i>Rop<\/i>: connecting <i>STXBP1<\/i> encephalopathy with \u03b1-synucleinopathies"],"prefix":"10.1093","volume":"33","author":[{"given":"Taro","family":"Matsuoka","sequence":"first","affiliation":[{"name":"Department of Pediatrics , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"},{"name":"Kyoto Prefectural University of Medicine , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Applied Biology, Kyoto Institute of Technology , Matsugasaki, Sakyo-ku, Kyoto 606-8585 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kasai","sequence":"additional","affiliation":[{"name":"Department of Neurology , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"},{"name":"Kyoto Prefectural University of Medicine , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takenori","family":"Tozawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"},{"name":"Kyoto Prefectural University of Medicine , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Iehara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"},{"name":"Kyoto Prefectural University of Medicine , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Chiyonobu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"},{"name":"Kyoto Prefectural University of Medicine , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"},{"name":"Department of Molecular Diagnostics and Therapeutics , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"},{"name":"Kyoto Prefectural University of Medicine , Graduate School of Medical Science, , 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,1]]},"reference":[{"key":"2024072221203005400_ref1","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1126\/science.287.5454.864","article-title":"Synaptic assembly of the brain in the absence of neurotransmitter secretion","volume":"287","author":"Verhage","year":"2000","journal-title":"Science"},{"key":"2024072221203005400_ref2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1471-4159.2010.06900.x","article-title":"Munc18-1 as a key regulator of neurosecretion","volume":"115","author":"Han","year":"2010","journal-title":"J Neurochem"},{"key":"2024072221203005400_ref3","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/ng.150","article-title":"De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy","volume":"40","author":"Saitsu","year":"2008","journal-title":"Nat Genet"},{"key":"2024072221203005400_ref4","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1212\/WNL.0000000000002457","article-title":"STXBP1 encephalopathy","volume":"86","author":"Stamberger","year":"2016","journal-title":"Neurology"},{"key":"2024072221203005400_ref5","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1093\/brain\/awy046","article-title":"Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 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