{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["121(17)"],"submitter":["Arvanitaki ES"],"pubmed_abstract":["DNA damage and neurodegenerative disorders are intimately linked but the underlying mechanism remains elusive. Here, we show that persistent DNA lesions in tissue-resident macrophages carrying an XPF-ERCC1 DNA repair defect trigger neuroinflammation and neuronal cell death in mice. We find that microglia accumulate dsDNAs and chromatin fragments in the cytosol, which are sensed thereby stimulating a viral-like immune response in <i>Er1<sup>Cx/-</sup></i> and naturally aged murine brain. Cytosolic DNAs are packaged into extracellular vesicles (EVs) that are released from microglia and discharge their dsDNA cargo into IFN-responsive neurons triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, we developed targeting EVs to deliver recombinant DNase I to <i>Er1<sup>Cx/-</sup></i> brain microglia in vivo. We show that EV-mediated elimination of cytosolic dsDNAs is sufficient to prevent neuroinflammation, reduce neuronal apoptosis, and delay the onset of neurodegenerative symptoms in <i>Er1<sup>Cx/-</sup></i> mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age-related neurodegeneration."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pagination":["e2317402121"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11047102"],"repository":["biostudies-literature"],"pubmed_title":["Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage."],"pmcid":["PMC11047102"],"pubmed_authors":["Tsakani E","Garinis GA","Arvanitaki ES","Nenedaki E","Kalafatakis I","Xydias D","Psilodimitrakopoulos S","Gkirtzimanaki K","Niotis G","Goulielmaki E","Rouska I","Karagogeos D","Stratakis E","Kefalogianni M","Schumacher B"],"additional_accession":[]},"is_claimable":false,"name":"Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage.","description":"DNA damage and neurodegenerative disorders are intimately linked but the underlying mechanism remains elusive. Here, we show that persistent DNA lesions in tissue-resident macrophages carrying an XPF-ERCC1 DNA repair defect trigger neuroinflammation and neuronal cell death in mice. We find that microglia accumulate dsDNAs and chromatin fragments in the cytosol, which are sensed thereby stimulating a viral-like immune response in <i>Er1<sup>Cx/-</sup></i> and naturally aged murine brain. Cytosolic DNAs are packaged into extracellular vesicles (EVs) that are released from microglia and discharge their dsDNA cargo into IFN-responsive neurons triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, we developed targeting EVs to deliver recombinant DNase I to <i>Er1<sup>Cx/-</sup></i> brain microglia in vivo. We show that EV-mediated elimination of cytosolic dsDNAs is sufficient to prevent neuroinflammation, reduce neuronal apoptosis, and delay the onset of neurodegenerative symptoms in <i>Er1<sup>Cx/-</sup></i> mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age-related neurodegeneration.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2025-04-26T07:58:22.249Z","creation":"2025-04-06T12:31:06.079Z"},"accession":"S-EPMC11047102","cross_references":{"pubmed":["38635632"],"doi":["10.1073/pnas.2317402121"]}}