Mutant Huntingtin disrupts neurogenic and astroglial programs via the EZH2–Let-7g–LIN28 axis with rescue by epigenetic modulators
Year: 2026
Type: article
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.
Source: Cell Death and Differentiation
Authors: JD Rosati, A. Casamassa, G. Ruotolo, AMG Giovenale, D. D’Andrea, G. Rotundo, A. D’Anzi, EM Turco, G. Bergonzoni, A. Visioli, I. Lombardi, RM Carletti, U. Cappucci, AM 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, AL Vescovi
Institutions: Casa Sollievo della Sofferenza, Saint Camillus International University of Health and Medical Sciences, University of Bristol, University of Trento, University of Milano-Bicocca, Sapienza University of Rome, Fondazione Santa Lucia, Roma Tre University, Istituto Nazionale Biostrutture e Biosistemi, Fondazione IRCCS Istituto Neurologico Carlo Besta, Italian Institute of Technology, University of Padua, Veneto Institute of Molecular Medicine, University of Florida Health, University of Florida, Link Campus University, Abu Dhabi Stem Cells Center
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,790
OpenAlex ID: W7168490934