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Publications

Journal Article Ahead of print

PubMed: 42463580 DOI: 10.1038/s41418-026-01812-8

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

Cell Death Differ

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

Affiliations

  • Cellular Reprogramming Unit, Neurological Disorders Research Group, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy.
  • UniCamillus University, Saint Camillus International University of Health Sciences, Rome, Italy.
  • Cellular Reprogramming Unit, Neurological Disorders Research Group, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy.
  • School of Engineering Mathematics and Technology, University of Bristol, Bristol, UK.
  • NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, Trento, Italy.
  • Stemgen Spa, Milano, Italy.
  • Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
  • Advanced Therapies Production Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy.
  • Laboratory of neurobiology and pathology, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.
  • Laboratorio d'Immunogenetica, Servizio di Medicina Trasfusionale, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
  • IRCCS Santa Lucia Foundation, Rome, Italy.
  • Hematopathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • Neurological Disorders Research Unit, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • Department of Science, Roma Tre University, Rome, Italy.
  • Biostructures and Biosystems National Institute (INBB), Roma, Italy.
  • Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • Cancer Stem Cells Unit, ISBReMIT, Fondazione IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • Inborn Errors of Morphogenesis Research Unit, Section of Developmental Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • Fondazione IRCCS Istituto Neurologico "C. Besta", Milano, Italy.
  • Huntington Disease Research Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  • Center for Life Nano & Neuro Scienze CLN2S@Sapienza-Italian Institute of Technology (IIT), Rome, Italy.
  • Department of Biomedical Sciences (DBS), University of Padova, Padova, Italy.
  • Veneto Institute of Molecular Medicine (VIMM), Padova, Italy.
  • Department of Neurosurgery, University of Florida, Gainesville, FL, USA.
  • Faculty of Medicine, Link Campus University, Rome, Italy.
  • Abu Dhabi Stem Cell Centre, Abu Dhabi, United Arab Emirates.

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.

MeSH

Cells, Cell Differentiation, Cell Death