FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase.

Abstract:

: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 p16INK4a , 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 p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a 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-p16INK4a 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.

journal_name

Aging Cell

journal_title

Aging cell

authors

Voisin J,Farina F,Naphade S,Fontaine M,Tshilenge KT,Galicia Aguirre C,Lopez-Ramirez A,Dancourt J,Ginisty A,Sasidharan Nair S,Lakshika Madushani K,Zhang N,Lejeune FX,Verny M,Campisi J,Ellerby LM,Neri C

doi

10.1111/acel.13226

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

e13226

issue

11

eissn

1474-9718

issn

1474-9726

journal_volume

19

pub_type

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