FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16<sup>INK4a</sup> increase
Jessica Voisin, Francesca Farina, Swati Naphade, Morgane Fontaine, Kizito‐Tshitoko Tshilenge, Carlos Galicia Aguirre, Alejandro Lopez‐Ramirez, Julia Dancourt, Aurélie Ginisty, Satish S. Nair, Kuruwitage Lakshika Madushani, Ningzhe Zhang, François‐Xavier Lejeune, Marc Verny, Judith Campisi, Lisa Ellerby, Christian Néri
Abstract
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 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.