The role of neuron-microglial interactions in Ataxia-Telangiectasia

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Cheng, Wen

Advisor dc:contributor.advisor

• Khoronenkova, Svetlana

• Ataxia-Telangiectasia
• ATM
• microglia
• neurite outgrowth
• neuroinflammation
• phagocytosis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/515095b2-f9fb-4f77-9851-17a53dc96afb/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.111436

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/372563