{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:42:20Z","timestamp":1792669340877,"version":"4.5.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntington\u2019s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. Although the mutant huntingtin protein is expressed from conception, clinical symptoms typically emerge in mid-adulthood. Imaging and molecular studies have raised the possibility that HD may involve neurodevelopmental abnormalities, but direct evidence at the single-cell level in the human fetal brain has been lacking. Here we investigated whether early, cell type\u2013specific transcriptional vulnerabilities arise during neurodevelopment, persist into adult pathology, and might be rescued.<\/jats:p>\n                  <jats:p>To address this, we performed single-cell transcriptomic profiling of the lateral ganglionic eminence (LGE) and cortex from a rare, anatomically intact human HD fetal brain, alongside matched controls. These data were complemented by an allelic series of HD mouse embryos and cross-compared with already published human post-mortem brains and brain organoid models\u2019 datasets.<\/jats:p>\n                  <jats:p>Neural progenitors displayed the highest number of differentially expressed genes in the human fetal brain, and were also impacted in the HD mouse model, where additional cell types displayed transcriptional alterations. Notably, human HD progenitor transcriptional signatures were moderately enriched in the developing mouse LGE. These progenitors exhibited increased expression of synaptic pathways coupled with reduced expression of cell maintenance genes. Cross-comparison with publicly available post-mortem HD datasets revealed that components of this transcriptional signature persist into adulthood. Furthermore, cellular interactions were found to mitigate these alterations, highlighting a potentially rescuable fetal-to-adult transcriptional signature with important implications for HD pathogenesis and therapeutic strategies.<\/jats:p>\n                  <jats:p>Together, these findings reinforce the view of HD as a disorder with developmental origins, in which early transcriptional changes may shape neuronal function while increasing susceptibility to later neurodegeneration.<\/jats:p>","DOI":"10.1093\/brain\/awag364","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:49:28Z","timestamp":1792583368000},"source":"Crossref","is-referenced-by-count":0,"title":["Progenitor transcriptional alterations link fetal and adult pathology in Huntington\u2019s disease"],"prefix":"10.1093","author":[{"given":"Mattia","family":"Battistella","sequence":"first","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Damaggio","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Conforti","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Scolz","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1192-0684","authenticated-orcid":false,"given":"Simone","family":"Maestri","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria Dickinson","family":"Bocchi","sequence":"additional","affiliation":[{"name":"The Center for Stem Cell Biology, Developmental Biology Program, Sloan-Kettering Institute for Cancer Research , New York, NY, 10065 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Iafolla","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Galimberti","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Morrocchi","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cordiglieri","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Vezzoli","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]},{"name":"ALEMBIC Advanced Light and Electron Microscopy BioImaging Center, IRCCS San Raffaele Scientific Institute , DIBIT 1, Milan, 20132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Lodato","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University , Milan, 20072 ,","place":["Italy"]},{"name":"IRCCS Humanitas Research Hospital , Rozzano, Milan, 20089 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0602-5335","authenticated-orcid":false,"given":"Valeria","family":"Ranzani","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Viale","sequence":"additional","affiliation":[{"name":"Sant\u2019Anna Hospital, Department of Obstetrics and Gynecology , Turin, 10126 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4573-9514","authenticated-orcid":false,"given":"Leslie","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, University of California , Irvine, CA, 92617 ,","place":["USA"]},{"name":"Department of Psychiatry and Human Behavior, University of California , Irvine, CA, 92617 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F","family":"Vogt","sequence":"additional","affiliation":[{"name":"CHDI Management\/CHDI Foundation , Princeton, NJ, 08540 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Felsenfeld","sequence":"additional","affiliation":[{"name":"CHDI Management\/CHDI Foundation , Princeton, NJ, 08540 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[{"name":"CHDI Management\/CHDI Foundation , Princeton, NJ, 08540 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Besusso","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0755-4917","authenticated-orcid":false,"given":"Elena","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan , Milan, 20133 ,","place":["Italy"]},{"name":"Istituto Nazionale Genetica Molecolare (INGM), Romeo ed Enrica Invernizzi , Milan, 20122 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