MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis

Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice, and patient-derived cells modeling TDP-43, SOD1, and C9orf72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioral abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived EVs that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.

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Publication Details

Journal
Brain
Published
2025-09-26
DOI
https://doi.org/10.1093/brain/awaf360
Citations
2
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
2.78

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article

MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis

Giorgina Scarduelli, Gabriella Viero, Alessio Zippo, Luca Tiberi et al.
2 citations
Brain
Amyotrophic Lateral Sclerosis Research
2.78
article

MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis

Giorgina Scarduelli, Gabriella Viero, Alessio Zippo, Luca Tiberi, Vera Mugoni, Manuela Basso, Serena Carra, Sabrina Invernizzi, Marco Milanese, Antonia Ratti, Elisa Ferracci, Laura Pasetto, Anna Barbieri, Michela Roccuzzo, Emanuele Buratti, Fulvio Chiacchiera, Vito D’Agostino, Sara Cappelli, Daniele Peroni, Nicola Ticozzi, F. Conci, Andrea Calvo, Maria Pennuto, Giulia Canarutto, Matteo Gianesello, Laura Soucek, Valentina Bonetto, Sama F. Sleiman, Michael Pancher, Jonathan R. Whitfield, Romina Belli, Marco Terenzio, Francesca Demichelis, Alice Migazzi, Luisa Donini, Beatrice Vignoli, Alessandra Bisio, Sergio Robbiati, Caterina Nardella, Alessia Soldano, Alessandro Quattrone, Silvano Piazza, Pamela J. Shaw, Maria Claudia Torrieri, Francesca Bacchetti, Davide Bressan, Chiara Valentini, Maurizio Grassano, Federico Verde, Paolo Vincenzo Fioretti, Katie M Bowden
article en
2 citations

Abstract

Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice, and patient-derived cells modeling TDP-43, SOD1, and C9orf72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioral abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived EVs that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.

Brain
Institució Catalana de Recerca i Estudis Avançats (ES), University of Modena and Reggio Emilia (IT), Hebron University (PS), Universitat Autònoma de Barcelona (ES), National Institutes of Health (US), Scuola Internazionale Superiore di Studi Avanzati (IT), University of Padua (IT), University of Trieste (IT), Okinawa Institute of Science and Technology Graduate University (JP), University of Milan (IT), University of Trento (IT), Mario Negri Institute for Pharmacological Research (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Veneto Institute of Molecular Medicine (IT), Sheffield Teaching Hospitals NHS Foundation Trust (GB), National Institute of Neurological Disorders and Stroke (US), Vall d'Hebron Hospital Universitari (ES), IRCCS Istituto Auxologico Italiano (IT), Institute of Biophysics (BG), FC Barcelona (ES), Ospedale Policlinico San Martino (IT), High Throughput Biology (United States) (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Turin (IT), Lebanese American University (LB), University of Genoa (IT), International Centre for Genetic Engineering and Biotechnology (IT), University of Sheffield (GB)
International Center for Genetic Engineering and Biotechnology, Università Degli Studi di Modena e Reggio Emila, Università degli Studi di Milano, Dipartimenti di Eccellenza, National Institute for Health and Care Research, European Commission, Ministero della Salute, Università degli Studi di Trento, Okinawa Institute of Science and Technology Graduate University, Fondazione Cassa Di Risparmio Di Trento E Rovereto, Center for Neurotechnology, University of Washington, European Regional Development Fund, NIHR Sheffield Biomedical Research Centre
Openalex Percentile: Top 8%
Amyotrophic Lateral Sclerosis Research
2.78
DOIOpen Access PDFOpenAlex
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