{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:54:06Z","timestamp":1785430446691,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,5]]},"group-title":"Developmental Biology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Wisconsin-Madison School of Medicine and Public Health"},{"id":[{"id":"https:\/\/ror.org\/00hwxbz16","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development"},{"name":"Fondation J\u00e9r\u00f4me Lejeune"},{"id":[{"id":"https:\/\/ror.org\/00rbzpz17","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016308","name":"Bpifrance","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016308","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Horizon 2020"},{"id":[{"id":"https:\/\/ror.org\/05cx8cy07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Dysregulated expression and activity of DYRK1A, dual specificity tyrosine phosphorylation regulated kinase 1A, is a feature of several neurodevelopmental and neurodegenerative diseases, including Down syndrome, DYRK1A syndrome, autism spectrum disorders, Alzheimer\u2019s disease, and Parkinson\u2019s disease. Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimer\u2019s disease, for example, but the ability to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell derived neural progenitor cells and neurons, where DYRK1A expression and activity are increased. Our results demonstrate that Leucettinib-21, a potent and selective low-molecular weight pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 neural progenitor cells and cortical neurons. We show for the first time that Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary Statement<\/jats:title>\n                  <jats:p>We show for the first time that Leucettinib-21, a pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in a human iPSC-derived neural cell culture model of Down syndrome.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.05.704014","type":"posted-content","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T08:55:15Z","timestamp":1770368115000},"source":"Crossref","is-referenced-by-count":0,"title":["Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 iPSC-derived neural cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0446-4294","authenticated-orcid":false,"given":"Nicole R.","family":"West","sequence":"first","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison, Madison WI, USA"},{"name":"Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9734-8163","authenticated-orcid":false,"given":"Mattias F.","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1767-0572","authenticated-orcid":false,"given":"Julien","family":"Dairou","sequence":"additional","affiliation":[{"name":"Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Universit\u00e9 Paris Cit\u00e9, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4018-5332","authenticated-orcid":false,"given":"Shawn","family":"MacGregor","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison, Madison WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahith","family":"Puthireddy","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison, Madison WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3511-4916","authenticated-orcid":false,"given":"Laurent","family":"Meijer","sequence":"additional","affiliation":[{"name":"Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0360-7145","authenticated-orcid":false,"given":"Anita","family":"Bhattacharyya","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison, Madison WI, USA"},{"name":"Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026021010152454000_2026.02.05.704014v1.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.110957"},{"key":"2026021010152454000_2026.02.05.704014v1.2","doi-asserted-by":"crossref","unstructured":"Aranda-Abreu, G. 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