{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T13:58:09Z","timestamp":1778335089618,"version":"3.51.4"},"reference-count":106,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-NS100529"],"award-info":[{"award-number":["R01-NS100529"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Taube Family Program in Regenerative Medicine Genome Editing for Huntington\u2019s Disease"},{"name":"Collaborative Center for X-linked Dystonia Parkinsonism"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Huntington\u2019s disease (HD) is a neurodegenerative disorder caused by an expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene, resulting in a mutant HTT (mHTT) protein. Although mHTT is expressed in all tissues, it significantly affects medium spiny neurons (MSNs) in the striatum, resulting in their loss and the subsequent motor function impairment in HD. While HD symptoms typically emerge in midlife, disrupted MSN neurodevelopment is important. To explore the effects of mHTT on MSN development, we differentiated HD-induced pluripotent stem cells (iPSCs) and isogenic controls into neuronal stem cells, and then generated a developing MSN population encompassing early, intermediate progenitors, and nascent MSNs. Single-cell RNA sequencing revealed that the developmental trajectory of MSNs in our model closely emulated the trajectory of human fetal striatal neurons. However, in the HD MSN cultures, several crucial genes required for proper MSN maturation were downregulated, including members of the DLX family of transcription factors. Our analysis also uncovered a progressive dysregulation of multiple HD-related pathways as MSNs developed, including the NRF2-mediated oxidative stress response and mitogen-activated protein kinase signaling. Using the transcriptional profile of developing HD MSNs, we searched the L1000 dataset for small molecules that induce the opposite gene expression pattern. We pinpointed numerous small molecules with known benefits in HD models and previously untested novel molecules. A top candidate, Cerulenin, partially restored the DARPP-32 levels and electrical activity in HD MSNs, and also modulated genes involved in multiple HD-related pathways.<\/jats:p>","DOI":"10.1093\/stmcls\/sxaf029","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T02:06:32Z","timestamp":1746669992000},"source":"Crossref","is-referenced-by-count":3,"title":["Cerulenin partially corrects the disrupted developmental transcriptomic signature in Huntington\u2019s disease striatal medium spiny neurons"],"prefix":"10.1093","volume":"43","author":[{"given":"Carlos","family":"Galicia Aguirre","sequence":"first","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["United States"]},{"name":"Leonard Davis School of Gerontology, University of Southern California , Los Angeles, CA 90893 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kizito-Tshitoko","family":"Tshilenge","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Battistoni","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Lopez-Ramirez","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swati","family":"Naphade","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["United 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D","family":"Mooney","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington , Seattle, WA 98109 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Melov","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["United States"]},{"name":"Leonard Davis School of Gerontology, University of Southern California , Los Angeles, CA 90893 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle E","family":"Ehrlich","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai , New York, NY 10029 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-7977","authenticated-orcid":false,"given":"Lisa M","family":"Ellerby","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["United States"]},{"name":"Leonard Davis School of Gerontology, University of Southern California , Los Angeles, CA 90893 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"2025072106112939700_CIT0001","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/0304-3940(91)90583-f","article-title":"Neuronal loss in layers V and VI of cerebral cortex in Huntington\u2019s disease","volume":"133","author":"Hedreen","year":"1991","journal-title":"Neurosci Lett."},{"key":"2025072106112939700_CIT0002","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1002\/ana.410270217","article-title":"Degeneration of pyramidal projection neurons in Huntington\u2019s disease 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