{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T21:47:15Z","timestamp":1780523235767,"version":"3.54.1"},"reference-count":50,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Korean government","doi-asserted-by":"publisher","award":["2020R1A5A2017323"],"award-info":[{"award-number":["2020R1A5A2017323"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government","doi-asserted-by":"publisher","award":["RS-2023-00223069"],"award-info":[{"award-number":["RS-2023-00223069"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government","doi-asserted-by":"publisher","award":["2120240615414"],"award-info":[{"award-number":["2120240615414"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Korean government","doi-asserted-by":"publisher","award":["RS-2025-02308336"],"award-info":[{"award-number":["RS-2025-02308336"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BK21 FOUR","award":["2020R1A5A2017323"],"award-info":[{"award-number":["2020R1A5A2017323"]}]},{"name":"BK21 FOUR","award":["RS-2023-00223069"],"award-info":[{"award-number":["RS-2023-00223069"]}]},{"name":"BK21 FOUR","award":["2120240615414"],"award-info":[{"award-number":["2120240615414"]}]},{"name":"BK21 FOUR","award":["RS-2025-02308336"],"award-info":[{"award-number":["RS-2025-02308336"]}]},{"name":"Ministry of Education, Korean government","award":["2020R1A5A2017323"],"award-info":[{"award-number":["2020R1A5A2017323"]}]},{"name":"Ministry of Education, Korean government","award":["RS-2023-00223069"],"award-info":[{"award-number":["RS-2023-00223069"]}]},{"name":"Ministry of Education, Korean government","award":["2120240615414"],"award-info":[{"award-number":["2120240615414"]}]},{"name":"Ministry of Education, Korean government","award":["RS-2025-02308336"],"award-info":[{"award-number":["RS-2025-02308336"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Animal and cellular models harboring SNCA gene mutations have been instrumental in synucleinopathy, but faithful human brain models remain limited. Here, we report the development of a human cerebral organoid (CO) model of synucleinopathy carrying the Ala53Thr mutation in SNCA (SNCAA53T). Using a human embryonic stem cell (hESC) line overexpressing SNCAA53T (A53T hESC line), we generated COs (A53T COs) that recapitulate hallmark features of synucleinopathy. These A53T COs exhibited elevated \u03b1-synuclein (\u03b1-Syn) expression, the increased phosphorylation of \u03b1-Syn, and Lewy body-like aggregations. Notably, we also observed the increased expression of phosphorylated tau and neurofibrillary tangle-like silver deposits, although amyloid \u03b2 expression and accumulation remained unchanged. To evaluate the utility of this model in drug screening, we treated A53T COs with synuclean D (SynD), an inhibitor of \u03b1-Syn aggregation, which significantly reduced both \u03b1-Syn and tau phosphorylation without affecting total \u03b1-Syn levels. Together, our findings establish a robust hESC-derived synucleinopathy CO model harboring the SNCAA53T mutation, demonstrating its potential as a valuable tool for therapeutic drug screening.<\/jats:p>","DOI":"10.3390\/cells14181436","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T09:43:41Z","timestamp":1757929421000},"page":"1436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modeling Synucleinopathy Using hESC-Derived Cerebral Organoids"],"prefix":"10.3390","volume":"14","author":[{"given":"So Jin","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Hee","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu Seog","family":"Choe","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale Stem Cell Center, Yale Child Study Center, Yale School of Medicine, New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye Seong","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.1016\/S1353-8020(13)70017-8","article-title":"alpha-Synucleinopathy phenotypes","volume":"20","author":"McCann","year":"2014","journal-title":"Parkinsonism Relat. 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