ArticleThe Journal of experimental medicine2022
DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.
Article in The Journal of experimental medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 73 citations in OpenAlex.
- Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease.Haematologica · 2024Trial
- Focal ischemia induces genome-wide accumulation of R-loops in the brain.Molecular therapy. Nucleic acids · 2026Article
- Medial temporal ageing-related tau astrogliopathy below 66 years is associated with neurodegeneration.Brain : a journal of neurology · 2026Article
- Biallelic variants inResearch square · 2026Article
- Interferon stimulatory DNA activates the DNA damage signaling through ATM and DNA-PK sensing.The Journal of biological chemistry · 2026Article
- When R-Loops Go Awry: Genome Instability and Neurological Diseases.The European journal of neuroscience · 2026Review
- Gut metabolites identified in cerebrospinal fluid of genetic interferonopathy support gut-brain endothelial dysfunction.Clinical & translational immunology · 2026Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Urea functions as a risk signal driving astrocyte-mediated neuroinflammation following stroke.Journal of neuroinflammation · 2025Article
- Activation and regulation of cGAS-STING signaling in cancer cells.Molecular cell · 2025Review
- Autocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers.Nature communications · 2025Article
- AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain.Nature communications · 2025Article
- Transcription-Replication Conflicts and Incomplete Replication as a Cause of Micronuclei-Driven Chromoanagenesis.Methods in molecular biology (Clifton, N.J.) · 2025Article
- The intersection of TREX1, cGAS, STING and the DNA damage theory of aging.Frontiers in aging · 2025Review
- AAV-mediated genome editing is influenced by the formation of R-loops.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- CNS disease associated with enhanced type I interferon signalling.The Lancet. Neurology · 2024Review
- Aberrant Enhanced NLRP3 Inflammasomes and Cell Pyroptosis in the Brains of Prion-Infected Rodent Models Are Largely Associated with the Proliferative Astrocytes.Molecular neurobiology · 2024Article
- The prototypical interferonopathy: Aicardi-Goutières syndrome from bedside to bench.Immunological reviews · 2024Review
- A novel STING variant triggers endothelial toxicity and SAVI disease.The Journal of experimental medicine · 2024Article
- R-loops and impaired autophagy trigger cGAS-dependent inflammation via micronuclei formation in Senataxin-deficient cells.Cellular and molecular life sciences : CMLS · 2024Article
Corrections and comments
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Authors and funding
24 authors at 7 institutions in 3 countries.
Funding
Abstract
Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.