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

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.

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Publication Details

Journal
Cell Death and Differentiation
Published
2026-07-16
DOI
https://doi.org/10.1038/s41418-026-01812-8
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
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article

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

Jessica Rosati, Manuela Basso, A. DʼAnzi, Ivan Lombardi et al.
Cell Death and Differentiation
Genetic Neurodegenerative Diseases
article

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

Jessica Rosati, Manuela Basso, A. DʼAnzi, Ivan Lombardi, Antonello Mai, Alessandro De Luca, D. Rotili, F. Squitieri, G Bergonzoni, Maria Pennuto, M. Gelati, Myriam Catalano, M Biagioli, RM Carletti, Silvia Di Angelantonio, Daniela Ferrari, O Palumbo, Sérgio Valente, Vincenzo Giambra, AL Vescovi, A. Rinaldi, A Del Casale, C. Bertollini, U. Cappucci, B. Reynolds, E. Binda, G. Ruotolo, M. Ciavarella, EM Turco, A. Migazzi, A. Casamassa, AMG Giovenale, G. Rotundo, D. D’Andrea, A. Visioli, L. Piacentini
article en

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.

Cell Death and Differentiation
Roma Tre University (IT), University of Padua (IT), University of Trento (IT), Casa Sollievo della Sofferenza (IT), University of Florida (US), University of Bristol (GB), Veneto Institute of Molecular Medicine (IT), Saint Camillus International University of Health and Medical Sciences (IT), Center for Nano Science and Technology (IT), Istituto Nazionale Biostrutture e Biosistemi (IT), Fondazione Santa Lucia (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Biogen (Italy) (IT), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Link Campus University (IT), University of Milano-Bicocca (IT), Sapienza University of Rome (IT), Abu Dhabi National Oil (United Arab Emirates) (AE)
Good health and well-being
Openalex Percentile: Top 13%
Genetic Neurodegenerative Diseases
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