{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:02:59Z","timestamp":1791241379234,"version":"4.1.0"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"37","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,9,13]]},"abstract":"<jats:p>\n                    Aggregated \u03b1-synuclein (\u03b1-SYN) proteins, encoded by the\n                    <jats:italic>SNCA<\/jats:italic>\n                    gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying \u03b1-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated \u03b1-SYN pathologies in human induced pluripotent stem cells (iPSCs)\u2013derived cortical organoids generated from patients with LBD with\n                    <jats:italic>SNCA<\/jats:italic>\n                    gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the\n                    <jats:italic>SNCA<\/jats:italic>\n                    gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration\u2013approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited \u03b1-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced \u03b1-SYN aggregation, and alleviated mitochondrial dysfunction in\n                    <jats:italic>SNCA<\/jats:italic>\n                    triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting \u03b1-SYN aggregation for LBD.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adk3700","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T14:00:35Z","timestamp":1726063235000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":25,"title":["Modeling Lewy body disease with\n                    <i>SNCA<\/i>\n                    triplication iPSC-derived cortical organoids and identifying therapeutic drugs"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7701-2371","authenticated-orcid":true,"given":"Yunjung","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, 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