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Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16<jats:sup>INK4a<\/jats:sup>, a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing <jats:italic>p16<jats:sup>INK4a<\/jats:sup><\/jats:italic> expression <jats:italic>via<\/jats:italic> the FOXO3 repression of the transcriptional modulator ETS2. Additionally, <jats:italic>p16<jats:sup>INK4a<\/jats:sup><\/jats:italic> promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3\u2010ETS2\u2010p16<jats:sup>INK4a<\/jats:sup> axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.<\/jats:p>","DOI":"10.1111\/acel.13226","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T16:48:08Z","timestamp":1604681288000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16<sup>INK4a<\/sup> increase"],"prefix":"10.1111","volume":"19","author":[{"given":"Jessica","family":"Voisin","sequence":"first","affiliation":[{"name":"Centre National de la Recherche Scientifique UMR 8256 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale ERL U1164 Assistance Publique\u2010H\u00f4pitaux de Paris Brain\u2010C Lab Sorbonne Universit\u00e9 Paris 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