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Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage

Proceedings of the National Academy of Sciences - PNAS, 2024-04, Vol.121 (17), p.e2317402121-e2317402121 [Peer Reviewed Journal]

Copyright National Academy of Sciences Apr 23, 2024 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.2317402121 ;PMID: 38635632

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Title:
Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage
Author: Arvanitaki, Ermioni S ; Goulielmaki, Evi ; Gkirtzimanaki, Katerina ; Niotis, George ; Tsakani, Edisona ; Nenedaki, Electra ; Rouska, Iliana ; Kefalogianni, Mary ; Xydias, Dionysios ; Kalafatakis, Ilias ; Psilodimitrakopoulos, Sotiris ; Karagogeos, Domna ; Schumacher, Björn ; Stratakis, Emmanuel ; Garinis, George A
Subjects: Age ; Animals ; Apoptosis ; Brain ; Cell death ; Chromatin ; Cytosol ; Damage ; Defence mechanisms ; Deoxyribonuclease ; Deoxyribonucleic acid ; DNA ; DNA Damage ; DNA repair ; ERCC1 protein ; Extracellular Vesicles ; Immune response ; Inflammation ; Lesions ; Macrophages ; Mice ; Microglia ; Microglia - metabolism ; Neurodegeneration ; Neurodegenerative diseases ; Neuroinflammatory Diseases ; Neurons - pathology ; Recombinants ; Signs and symptoms ; Vesicles
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2024-04, Vol.121 (17), p.e2317402121-e2317402121
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 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 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 mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age-related neurodegeneration.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.2317402121
PMID: 38635632
Source: Geneva Foundation Free Medical Journals at publisher websites
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Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage

Copyright National Academy of Sciences Apr 23, 2024 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.2317402121 ;PMID: 38635632

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