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

Abstract

Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis and frontotemporal dementia 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 modelling 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 behavioural abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived extracellular vesicles 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.

Metadata

Item Type:	Article
Authors/Creators:	Fioretti, P.V. Barbieri, A. Migazzi, A. Bressan, D. https://orcid.org/0000-0003-4757-2535 Grassano, M. Donini, L. Roccuzzo, M. Torrieri, M.C. Conci, F. Ferracci, E. Invernizzi, S. Bowden, K.M. Bacchetti, F. Cappelli, S. Peroni, D. Belli, R. Pancher, M. Mugoni, V. Scarduelli, G. Gianesello, M. Pasetto, L. Canarutto, G. Carra, S. Soldano, A. Bisio, A. Robbiati, S. Valentini, C. Nardella, C. Piazza, S. D’Agostino, V.G. Quattrone, A. https://orcid.org/0000-0003-3333-7630 Sleiman, S. Whitfield, J.R. Soucek, L. Vignoli, B. Viero, G. Tiberi, L. Zippo, A. Demichelis, F. https://orcid.org/0000-0002-8266-8631 Bonetto, V. https://orcid.org/0000-0003-0456-2054 Milanese, M. Buratti, E. Verde, F. Ticozzi, N. https://orcid.org/0000-0001-5963-7426 Calvo, A. https://orcid.org/0000-0002-5122-7243 Ratti, A. https://orcid.org/0000-0002-4264-6614 Shaw, P.J. https://orcid.org/0000-0002-8925-2567 Terenzio, M. Chiacchiera, F. Pennuto, M. https://orcid.org/0000-0001-8634-0767 Basso, M. https://orcid.org/0000-0002-9278-8960
Copyright, Publisher and Additional Information:	© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by- nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
Keywords:	MYC; TDP-43; amyotrophic lateral sclerosis; astrocytes; extracellular vesicles; gliosis; Amyotrophic Lateral Sclerosis; Animals; Mice; Humans; Neuroglia; Gliosis; Neurons; Cell Communication; Mice, Transgenic; Proto-Oncogene Proteins c-myc; DNA-Binding Proteins; Astrocytes; C9orf72 Protein; Disease Models, Animal; Superoxide Dismutase-1
Dates:	Submitted: 16 December 2024 Accepted: 30 August 2025 Published (online): 26 September 2025 Published: May 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Funding Information:	Funder Grant number National Institute for Health and Care Research NIHR203321
Date Deposited:	03 Sep 2026 14:31
Last Modified:	03 Sep 2026 14:31
Status:	Published
Publisher:	Oxford University Press (OUP)
Refereed:	Yes
Identification Number:	10.1093/brain/awaf360
Related URLs:	PubMed URL Dataset Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:245015

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

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

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