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oai:www.repository.cam.ac.uk:1810/3725632024-08-23T00:42:50Zcom_1810_219476com_1810_256062col_1810_219483

The role of neuron-microglial interactions in Ataxia-Telangiectasia https://doi.org/10.17863/CAM.111436 Cheng, Wen Khoronenkova, Svetlana Ataxia-Telangiectasia (A-T) is a genome instability disorder characterised by progressive loss of cerebellar neurons, as well as metabolic and immunological deficits. A-T is caused by mutations in ATM kinase, a critical regulator of cellular response to DNA damage, oxidative stress, and more broadly changes in homeostasis. Accumulating evidence indicates that dysregulated interactions between neurons and non-neuronal cell types, such as the resident macrophages of the central nervous system called microglia, may underlie the neurological deficits observed in A-T. The loss of ATM has been shown to drive cell-intrinsic microglial dysfunction, however, it remains unknown whether this dysfunction affects neuron-microglial interactions and how it might contribute to cerebellar neurodegeneration in ATM deficiency. This thesis aims to investigate the roles of ATM kinase in neuron-microglial interactions using co-cultures of human post-mitotic neurons and microglia-like cells. This work demonstrates that loss of ATM in microglia promotes neuronal apoptosis, whereas neuronal ATM deficiency triggers microglial clustering in co-cultures and local damage to the neuronal network. Such damage may arise from excessive engulfment of neuronal compartments in combination with aberrant production of pro-inflammatory mediators by microglia. This study also discovers that loss of ATM results in compromised microglia-mediated neurite outgrowth, likely driven by excessive secretion of inflammatory compounds and insufficient production of growth factors. Indeed, expression of pro-inflammatory mediators, such as IL-6 and IL-1β, is increased, whereas expression of growth factors, such as FGFs and fractalkine, is reduced in ATM-deficient co-cultures. The establishment of neurite patterns is crucial for the functional specification of neurons during development. Therefore, aberrant neuron-microglial interactions in ATM deficiency may result in abnormal neurite pattern establishment, predicting neuronal dysfunction and degeneration. Overall, this work indicates that dysregulated neuron-microglial crosstalk in ATM kinase deficiency may drive abnormal neurodevelopment, providing novel insights into the mechanisms underlying neurological deficits of Ataxia-Telangiectasia. University of Cambridge 2024-02-01 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/372563 embargo 2025-08-22 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/6192ed0e-e9e3-4cc1-a037-a53de6112a67/download 24bf3e54b6c45928782d139f57e1502e https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/515095b2-f9fb-4f77-9851-17a53dc96afb/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Ataxia-Telangiectasia ATM microglia neurite outgrowth neuroinflammation phagocytosis