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Identifier

000434255

Title

DNA damage – induced inflammation in neurodegeneration

Alternative Title

Μελέτη του ρόλου της φλεγμόνης που επάγεται από την συσσώρευση γενετικών βλαβών

Author

Τσακάνι, Εντισόνα Π.

Thesis advisor

Γαρίνης, Γεώργιος

Abstract

Microglia cells are the tissue-resident macrophages of the Central Nervous System (CNS), which therefore act as the first and main form of active immune defense in the brain. Microglia promote phagocytic clearance, provide trophic support to ensure tissue repair, protect neurons and maintain brain homeostasis. In this study we used a monocyte/macrophage-specific Ercc1-/- mouse (Cx3cr1-Cre) model, which was generated for the investigation of the consequences of DNA repair impairment in tissue-resident macrophages. Led by the animal’s phenotype, which resembled cerebellar ataxia- like neuropathology, we shifted our focus on microglia in the cerebellum. Here, we demonstrate that DNA damage accumulation in microglia cells, results in the presence of cytoplasmic damaged chromatin fragments, potentially through nucleophagy. Cytoplasmic DNA not only triggers microglia priming in a cell autonomous manner through type I IFN response, but is also carried in exosomes, and therefore get secreted to the extracellular space. We suggest that the combination of type I IFN response activation and exososomal secretion promotes Purkinje cell apoptosis and thus neurodegeneration. Overall, this research aims at investigating if DNA damage accumulation occuring in microglia affects or results in age-related neuropathology. In vivo experiments, using exosomes loaded with DnaseI were also performed as an attempt for potential therapy and reversion of the animal’s phenotype.

Language

English, Greek

Subject

Microglia

Γενετικές βλάβες

Μικρογλοία

Νευροεκφυλισμός

Φλεγμόνη

Issue date

2020-11-27

Collection

School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses