biostudies-literatureBourseguin JRoyal Society Sir Henry Dale FellowshipCancer Research UKNIA NIH HHSIsaac Newton TrustNIHRoyal SocietyWellcome-Beit PrizeWellcome Trust ISSFCharles H. Hood Child Health FoundationAstraZeneca PhD studentshipCRUK Cambridge CentreSuh Kyungbae FoundationAstraZenecaUniversity of Cambridge Joint Research Grants SchemeWellcome TrustNIGMS NIH HHS2700-2718https://www.ebi.ac.uk/biostudies/studies/S-EPMC8934660biostudies-literatureUnknown50(5)The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterized 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 thNucleic acids researchPersistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction.PMC8934660T32GM007753DP2 AG072437107643/B/15/ZT32 GM007753S_4090107643/B/15/ARGS/R1/201043R00 AG05474828759Lai JJeffries AMHardy LLodato MAKhoronenkova SVBourseguin JCheng WLee EATalbot EfalsePersistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction.The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterized 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 th2022-01-01T00:00:00Z2022 Mar2025-04-05T11:07:10.962Z2025-04-05T11:07:10.962ZS-EPMC89346603521238510.1093/nar/gkac104