{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/372563"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/372563","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The role of neuron-microglial interactions in Ataxia-Telangiectasia","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Cheng, Wen"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Khoronenkova, Svetlana"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-02-01","date_published":"2024-02-01","updated_at":"2026-07-22T22:24:14Z","subjects":["Ataxia-Telangiectasia","ATM","microglia","neurite outgrowth","neuroinflammation","phagocytosis"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/515095b2-f9fb-4f77-9851-17a53dc96afb/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.111436","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Khoronenkova, Svetlana"]},{"key":"dc:creator","label":"Author","values":["Cheng, Wen"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2024-02-01"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/372563"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Ataxia-Telangiectasia","ATM","microglia","neurite outgrowth","neuroinflammation","phagocytosis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/515095b2-f9fb-4f77-9851-17a53dc96afb/download","https://www.rioxx.net/licenses/all-rights-reserved/"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2025-08-22"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.111436"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/6192ed0e-e9e3-4cc1-a037-a53de6112a67/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["24bf3e54b6c45928782d139f57e1502e","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["The role of neuron-microglial interactions in Ataxia-Telangiectasia"]}]}],"canonical_facts":{"dc:contributor.advisor":["Khoronenkova, Svetlana"],"dc:creator":["Cheng, Wen"],"dc:date.issued":["2024-02-01"],"dc:description.abstract":["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."],"dc:format.checksum.md5":["24bf3e54b6c45928782d139f57e1502e","87eda9de84448d1f82354d60eee3eb5f"],"dc:identifier.doi":["https://doi.org/10.17863/CAM.111436"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/6192ed0e-e9e3-4cc1-a037-a53de6112a67/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/372563"],"dc:rights":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/515095b2-f9fb-4f77-9851-17a53dc96afb/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"dc:rights.embargodate":["2025-08-22"],"dc:rights.embargotype":["embargo"],"dc:subject":["Ataxia-Telangiectasia","ATM","microglia","neurite outgrowth","neuroinflammation","phagocytosis"],"dc:title":["The role of neuron-microglial interactions in Ataxia-Telangiectasia"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:14Z"}