Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction
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Authors
Bourseguin, Julie
Cheng, Wen
Talbot, Emily
Hardy, Liana
Lai, Jenny
Jeffries, Ailsa M
Lodato, Michael A
Lee, Eunjung Alice
Khoronenkova, Svetlana V
Publication Date
2022-03-21Journal Title
Nucleic Acids Research
ISSN
0305-1048
Publisher
Oxford University Press
Volume
50
Issue
5
Pages
2700-2718
Language
eng
Type
Article
This Version
VoR
Metadata
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Bourseguin, J., Cheng, W., Talbot, E., Hardy, L., Lai, J., Jeffries, A. M., Lodato, M. A., et al. (2022). Persistent DNA damage associated with ATM kinase deficiency
promotes microglial dysfunction. Nucleic Acids Research, 50 (5), 2700-2718. https://doi.org/10.1093/nar/gkac104
Description
Funder: Charles H. Hood Child Health Foundation
Funder: Wellcome Trust ISSF
Funder: CRUK Cambridge Centre
Funder: AstraZeneca PhD studentship
Funder: Suh Kyungbae Foundation
Funder: University of Cambridge Joint Research Grants Scheme
Funder: Isaac Newton Trust
Abstract
The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human
microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neuronal material. Activation of the RELB/p52 pathway in
ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. Activation of non-canonical NF-κB signalling is also observed in cerebellar microglia of individuals with Ataxia-telangiectasia. These results provide insights into the underlying
mechanisms of aberrant microglial behaviour in ATM deficiency, potentially contributing to neurodegeneration in Ataxia-telangiectasia.
Sponsorship
Wellcome Trust (107643/Z/15/A)
Royal Society (RGS\R1\201043)
Identifiers
35212385, PMC8934660
External DOI: https://doi.org/10.1093/nar/gkac104
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335426
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