FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16 INK4a increase.

Autor: Voisin J; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Farina F; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Naphade S; Buck Institute for Research on Aging, Novato, CA, USA., Fontaine M; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Tshilenge KT; Buck Institute for Research on Aging, Novato, CA, USA., Galicia Aguirre C; Buck Institute for Research on Aging, Novato, CA, USA., Lopez-Ramirez A; Buck Institute for Research on Aging, Novato, CA, USA., Dancourt J; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Ginisty A; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Sasidharan Nair S; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Lakshika Madushani K; Buck Institute for Research on Aging, Novato, CA, USA., Zhang N; Buck Institute for Research on Aging, Novato, CA, USA., Lejeune FX; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Verny M; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France., Campisi J; Buck Institute for Research on Aging, Novato, CA, USA.; Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Ellerby LM; Buck Institute for Research on Aging, Novato, CA, USA., Neri C; Centre National de la Recherche Scientifique UMR 8256, Institut National de la Santé et de la Recherche Médicale ERL U1164, Assistance Publique-Hôpitaux de Paris, Brain-C Lab, Sorbonne Université, Paris, France.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2020 Nov; Vol. 19 (11), pp. e13226. Date of Electronic Publication: 2020 Nov 06.
DOI: 10.1111/acel.13226
Abstrakt: Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. 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 INK4a , 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 p16 INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16 INK4a 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-ETS2-p16 INK4a 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.
(© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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