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<p>Ataxia Telangiectasia (A-T) is a neurodegenerative disorder characterized by early onset, cerebellar ataxia and progressive motor decline. The causative gene, <i>ATM</i> (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 <i>Atm</i> allele combined with a null allele (<i>Atm</i><sup><i>KDF/CNS−KO</i></sup>), 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 <i>Atm</i><sup><i>KDF/CNS−KO</i></sup> 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 <i>Atm</i><sup><i>KDF/CNS−KO</i></sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Francesca Montarolo,
  • Luna Berrino,
  • Anita Maria Rominto,
  • Matilde Loddo,
  • Ilaria Balbo,
  • Anastasia Ricci,
  • Giulia Pia Servetto,
  • Ginevra Mango,
  • Kenta Yamamoto,
  • Roberta Parolisi,
  • Antonio Bertolotto,
  • Ruggero Vigliaturo,
  • Michele Menotta,
  • Shan Zha,
  • Filippo Tempia,
  • Eriola Hoxha

摘要

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.