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Mechanisms of cytosolic DNA sensing and neuroinflammation in ataxia-telangiectasia


Type

Thesis

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Authors

Talbot, Emily 

Abstract

Monogenic genome instability disorders are caused by loss-of-function mutations in genes critical for the DNA damage response. These disorders commonly present with neurological disease, exemplifying the importance of preserving genome stability in the central nervous system (CNS). Ataxia-telangiectasia (A-T) is a prototypical genome instability syndrome caused by loss-of-function mutations in ATM kinase, a master regulator of the cellular response to DNA damage, including DNA double stand breaks and oxidative stress. A-T is a multisystemic disease that manifests in the CNS as cerebellar degeneration, leading to debilitating ataxia. ATM deficiency and the consequential persistent DNA damage is increasingly associated with dysfunction of microglia, the resident macrophages of the CNS. Microglia-driven neurotoxicity is also linked with neurodegeneration in A-T, however, the molecular mechanisms by which ATM loss regulates microglial function remain elusive. Genotoxic stress can induce sterile inflammation via release of nuclear DNA into the cytosol, activating the cytosolic DNA sensing cGAS-STING pathway. Utilising genetic knockout of ATM or selective kinase inhibition in human microglial cell models, this thesis demonstrates that DNA damage associated with ATM deficiency drives chronic inflammation in a cGAS-STING-dependent manner. This work further shows that cGAS-STING activation occurs primarily via recognition of micronuclei which can form during mitosis in cells harbouring unresolved DNA damage. Furthermore, this work highlights that loss of kinase activity is a more potent driver of inflammation than loss of full-length ATM, in line with heightened genotoxicity of catalytically inactive ATM. Investigation of how STING activation perturbs homeostatic microglial processes in ATM deficiency reveals that STING may regulate microglial migration, but not phagocytosis or apoptosis. Following loss of ATM function, STING signalling also drives production of potentially neurotoxic inflammatory mediators and chemokines, including CCL5 and CXCL10. As these chemokines are implicated in recruitment of peripheral immune cells, it could be speculated that chronic STING-dependent chemokine production may exacerbate inflammation by promoting immune infiltration into the CNS. Overall, this work implicates microglial cytosolic DNA sensing as a driver of neuroinflammation and provides a rationale for exploring the therapeutic potential of STING inhibition in disorders attributed to genome instability in the CNS.

Description

Date

2023-03-30

Advisors

Khoronenkova, Svetlana

Keywords

Genome instability, Microglia, Neuroinflammation, Cytosolic DNA

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
AstraZeneca