ATM-kinase deficiency triggers early multi-compartment remodeling of the cerebellar microenvironment.

Overview

1. Department of Neuroscience, University of Torino, Via Cherasco 15, 10125 Torino, Italy
2. Neuroscience Institute Cavalieri Ottolenghi (NICO), Regione Gonzole 10, 10043 Orbassano, TO Italy
3. Department of Neurology, College of Physicians and Surgeons, Columbia University, 10032 New York, NY USA
4. Initiative for Columbia Ataxia and Tremor, Columbia University, New York, NY 10032 USA
5. Department of Biomolecular Sciences, University of Urbino “Carlo Bo” Campus Scientifico Enrico Mattei, Via Cà le Suore, 2, 61029 Urbino, PU Italy
6. Department of Earth Sciences, University of Torino, via Valperga Caluso 35, 10125 Torino, Italy
7. Pathobiology Ph.D. Program, Vagelos College for Physicians and Surgeons, Columbia University, New York, NY 10032 USA
8. Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates “G. Scansetti”, University of Torino, via Pietro Giuria 9, 10125 Torino, Italy
9. Institute for Cancer Genes, Vagelos College for Physicians and Surgeons, Columbia University, New York, NY 10032 USA

Abstract

Ataxia Telangiectasia (A-T) is a neurodegenerative disorder characterized by early onset, cerebellar ataxia and progressive motor decline. The causative gene, ATM (A-T Mutated), encodes a Ser/Thr kinase, that belongs to the phosphoinositide 3-kinase-related protein kinase family and is crucial for the response to DNA double-strand breaks. While ATM is classically known for its role in the DNA damage response, increasing evidence points to its critical function in maintaining cellular homeostasis, particularly in the central nervous system (CNS). Yet the mechanisms linking ATM-kinase deficiency to cerebellar circuit dysfunction remain poorly defined. Using a CNS Nestin-Cre-restricted mouse model carrying a kinase-dead Atm allele combined with a null allele (AtmKDF/CNS−KO), we integrated proteomics, structural and ultrastructural analyses, electrophysiology, and behavioral testing to understand how the loss of Atm kinase activity influence the cerebellar microenvironment from the earliest stages of the disease. Proteomic profiling revealed alterations across four major pathways in AtmKDF/CNS−KO mice, such as disorganization of the extracellular matrix (ECM), astrocytosis, downregulation of myelin and oligodendrocyte lineage proteins and changes in neuronal excitability. Histological and electron microscopy analyses confirmed increased ECM deposition, astrocytosis and reduction of myelin content without axonal or oligodendrocyte loss, consistent with impaired myelination at early stages. These microenvironmental changes were associated to Purkinje cell dark cell degeneration and increased intrinsic excitability, demonstrating early circuit dysfunction in the absence of overt neuronal loss. Consistently, the compromised cerebellar output is confirmed by the progressive motor impairment developed by AtmKDF/CNS−KO mice. Our findings indicate that Atm kinase deficiency disrupts cerebellar homeostasis through interconnected and bidirectional mechanisms involving ECM remodeling, astrocytosis, impaired oligodendrocyte functioning and altered intrinsic excitability, reflecting a network level destabilization of the cerebellar microenvironment.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40478-026-02332-9.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• figshare:33159811, at figshare; found in DataCite

Data availability

All data supporting the findings of this study are available from the corresponding author upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Funding: added Fondazione CRT; Dipartimenti di Eccellenza; Banca d'Italia; Università degli Studi di Torino

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 16 authors, 6 keywords, 9 MeSH terms, 62 references, 13 RRIDs.

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This paper

Montarolo, F., Berrino, L., Rominto, A. M., Loddo, M., Balbo, I., Ricci, A., Servetto, G. P., Mango, G., Yamamoto, K., Parolisi, R., Bertolotto, A., Vigliaturo, R., Menotta, M., Zha, S., Tempia, F., & Hoxha, E. (2026). ATM-kinase deficiency triggers early multi-compartment remodeling of the cerebellar microenvironment. Acta neuropathologica communications, 14(1), 161. https://doi.org/10.1186/s40478-026-02332-9

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