Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2-Let-7g-LIN28 axis with rescue by epigenetic modulators.

Authors

J D Rosati, A Casamassa, G Ruotolo, Amg Giovenale, D D'Andrea, G Rotundo, A D'Anzi, E M Turco, G Bergonzoni, A Visioli, I Lombardi, R M Carletti, U Cappucci, A M Casale, A Migazzi, M Ciavarella, A Rinaldi, C Bertollini, V Giambra, A De Luca, D Rotili, S Valente, E Binda, O Palumbo, M Gelati, F Squitieri, L Piacentini, D Ferrari, S Di Angelantonio, M Catalano, A Mai, M Biagioli, M Basso, M Pennuto, B Reynolds, A L Vescovi

Published in

Cell death and differentiation. Jul 16, 2026. Epub Jul 16, 2026.

Abstract

The molecular mechanisms by which mutant huntingtin (mHTT) drives pathogenesis in Huntington's disease (HD) remain incompletely defined. Here we show that neurogenesis is disrupted at multiple stages of lineage progression in both rodent and human neural stem cell (NSC) models of HD. We identify a previously unrecognized phenotype characterized by aberrant expansion of early multipotent progenitors coupled to a profound defect in astrogliogenesis, whereby HD astrocytes fail to express glial fibrillary acidic protein (GFAP). Mechanistically, this defect arises from dysregulation of an epigenetic regulatory axis involving EZH2 and LIN28 upregulation together with reduced expression of the mature let-7g microRNA. Epigenetic pharmacological interventions, targeting this pathway at distinct nodes-through EZH2 modulation, let-7g restoration, or LIN28 inhibition-rescued astroglial differentiation in human HD cells and improved motor function in a Drosophila HD model. Our findings suggest that mHTT might trigger a dual-phase astroglial failure: an early developmental impairment followed by a collapse of regenerative gliogenesis. This bimodal mechanism proposes astrocytic dysfunction as a central driver of HD pathogenesis. Finally, we identify a panel of clinically relevant epigenetic compounds that, by converging on distinct targets within this axis, hold promise for stage-spanning therapeutic strategies capable of modifying disease trajectory.

PMID:
42463580
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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