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Related Experiment Video

Updated: Oct 2, 2025

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
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Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction.

Julie Bourseguin1, Wen Cheng1, Emily Talbot1

  • 1Department of Biochemistry, University of Cambridge, 80 Tennis Court road, CambridgeCB2 1GA, UK.

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|February 25, 2022
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Summary

DNA damage in Ataxia-telangiectasia (ATM deficiency) causes dysfunctional microglia to excessively clear neurons. This neuroinflammation involves the RELB/p52 pathway, offering insights into neurodegeneration.

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Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by genome instability and progressive cerebellar neurodegeneration.
  • Mutations in the ATM (Ataxia-Telangiectasia Mutated) kinase gene are the primary cause of A-T.
  • Microglia, the resident immune cells of the central nervous system, play a critical role in brain homeostasis and disease.

Purpose of the Study:

  • To investigate the impact of ATM loss and associated DNA damage on human microglial function.
  • To elucidate the molecular mechanisms underlying microglial dysfunction in the context of ATM deficiency.
  • To explore the potential contribution of microglial dysfunction to neurodegeneration in Ataxia-telangiectasia.

Main Methods:

  • Analysis of DNA damage in ATM-deficient cells.
  • Assessment of microglial behavior, including phagocytic activity.
  • Investigation of the role of the RELB/p52 non-canonical NF-κB pathway and NIK kinase in microglial dysfunction.
  • Examination of cerebellar microglia from individuals with Ataxia-telangiectasia.

Main Results:

  • ATM loss and consequent DNA damage induce dysfunctional behavior in human microglia.
  • Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB pathway.
  • This pathway activation, driven by persistent DNA damage and NIK kinase, leads to excessive neuronal material clearance.
  • Non-canonical NF-κB signaling activation is confirmed in cerebellar microglia of A-T patients.

Conclusions:

  • Persistent DNA damage in ATM-deficient microglia activates the RELB/p52 non-canonical NF-κB pathway.
  • This aberrant microglial activation contributes to excessive phagocytosis and potentially neurodegeneration in Ataxia-telangiectasia.
  • Understanding these mechanisms offers potential therapeutic targets for neurodegenerative diseases associated with ATM deficiency.