ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia

Lai, Jenny; Kim, Junho; Jeffries, Ailsa M.; Tolles, Allie; Chittenden, Thomas; Buckley, Patrick G.; Yu, Timothy W.; Lodato, Michael A.; Lee, Eunjung Alice

doi:10.1101/2021.09.09.459619

Cited by 8 publications

(22 citation statements)

References 103 publications

(94 reference statements)

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“…Next, we compared the list of transcripts found to be differentially expressed in CMVMJD135 mice with 40 different datasets of previously reported DEGs, which include, among others, data on the microglial signature program [ 49 , 50 ] on other neurodegenerative disorders [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], aging [ 38 , 51 , 63 ], disease-associated microglia (DAM) [ 64 ], and injury-related microglia [ 38 , 51 ]. We found a significant overlap with only 3 of the 40 published gene sets, namely with the DEGs seen in microglia of a mouse model of amyotrophic lateral sclerosis (ALS), the SOD1 G93A mouse model [ 52 ]; of a mouse model of Alzheimer disease (AD), the App NL-G-F/NL-G-F mouse model [ 52 ]; and with a list of microglial genes highly expressed and/or affected in different neuroinflammatory conditions [ 65 ] ( Figure S13 in Supplementary Results and Supplementary Data 2 ).…”

Section: Resultsmentioning

confidence: 99%

Profiling Microglia in a Mouse Model of Machado–Joseph Disease

et al. 2022

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Microglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado–Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.

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Section: Resultsmentioning

confidence: 99%

Profiling Microglia in a Mouse Model of Machado–Joseph Disease

et al. 2022

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“…To determine whether the NF-κB pathway is regulated in human disease, we analysed the microglia transcriptomes from a single-nucleus RNA-sequencing dataset of human cerebellum (CB) from individuals with A–T and healthy controls ( 33 ). Enrichment analyses of canonical and non-canonical NF-κB pathway gene sets of A–T versus control cerebellar microglia were performed.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, in murine model of A–T, microglia-induced neurotoxicity was dependent on secretion of IL-1β ( 12 ). In addition, microglia from individuals with A–T show enrichment of genes associated with cytokine production ( 33 ). We propose that initial activation of the non-canonical NF-κB pathway in the presence of unrepaired DNA damage could promote the release of cytokines in the extracellular compartment, thus establishing the local pro-inflammatory environment.…”

Section: Discussionmentioning

confidence: 99%

“…Human microglia single-nucleus RNA-sequencing data from A–T and control cerebellum were obtained as described ( 33 ). Canonical and non-canonical NF-κB pathway gene sets were curated from the literature ( 34 , 35 ).…”

Section: Methodsmentioning

confidence: 99%

“…To determine the enrichment of each gene set, we implemented a t- score permutation test following a statistical approach ( 37 ). T- scores for each gene were obtained from the differential gene expression analysis of A–T compared to control cerebellar microglia ( 33 ). Briefly, the analysis was performed using edgeR.…”

Section: Methodsmentioning

confidence: 99%

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Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction

Bourseguin

Cheng

Talbot

et al. 2022

Nucleic Acids Research

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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 the underlying mechanisms of aberrant microglial behaviour in ATM deficiency, potentially contributing to neurodegeneration in Ataxia–telangiectasia.

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Disproportionate Expression of ATM in Cerebellar Cortex During Human Neurodevelopment

et al. 2023

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Cerebellar neurodegeneration is a classical feature of ataxia telangiectasia (A-T), an autosomal recessive condition caused by loss-of-function mutation of the ATM gene, a gene with multiple regulatory functions. The increased vulnerability of cerebellar neurones to degeneration compared to cerebral neuronal populations in individuals with ataxia telangiectasia implies a specific importance of intact ATM function in the cerebellum. We hypothesised that there would be elevated transcription of ATM in the cerebellar cortex relative to ATM expression in other grey matter regions during neurodevelopment in individuals without A-T. Using ATM transcription data from the BrainSpan Atlas of the Developing Human Brain, we demonstrate a rapid increase in cerebellar ATM expression relative to expression in other brain regions during gestation and remaining elevated during early childhood, a period corresponding to the emergence of cerebellar neurodegeneration in ataxia telangiectasia patients. We then used gene ontology analysis to identify the biological processes represented in the genes correlated with cerebellar ATM expression. This analysis demonstrated that multiple processes are associated with expression of ATM in the cerebellum, including cellular respiration, mitochondrial function, histone methylation, and cell-cycle regulation, alongside its canonical role in DNA double-strand break repair. Thus, the enhanced expression of ATM in the cerebellum during early development may be related to the specific energetic demands of the cerebellum and its role as a regulator of these processes.

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ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia

Cited by 8 publications

References 103 publications

Profiling Microglia in a Mouse Model of Machado–Joseph Disease

Profiling Microglia in a Mouse Model of Machado–Joseph Disease

Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction

Disproportionate Expression of ATM in Cerebellar Cortex During Human Neurodevelopment

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