Investigating the role of ATM kinase in synapse development and homeostasis

Taylor, Matthew James ORCID: 0000-0003-3055-4453 (2024). Investigating the role of ATM kinase in synapse development and homeostasis. University of Birmingham. Ph.D.

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Abstract

Mutations in Ataxia-telangiectasia mutated (ATM), a master regulator of the DNA damage response (DDR), result in early-onset cerebellar ataxia and neurodegeneration. There is increasing evidence of a neuronal-specific role for this ubiquitous kinase, and ATM both localises to synapses and is required for long-term potentiation. The mechanisms underlying its role in synaptic development and function are, however, unclear. Using the Drosophila third instar larval neuromuscular junction (NMJ), this thesis uncovers the requirement for presynaptic Drosophila ATM (dATM) in neurodevelopment, distinct from its function in the DDR. As with mammalian ATM, neuronal GFP-tagged dATM is predominantly cytosolic, forming foci within axons and synapses. Two processes which are held in delicate balance during the fine tuning of synapse development are oxidative stress and autophagy – each can promote synapse expansion, yet in excess are deleterious. Previous work has shown that cytosolic ATM interconnects these processes. Consistent with this, this thesis demonstrates that the function of presynaptic dATM involves its coordination of ROS signalling and autophagy through the conservation of the ATM-AMPK axis. dATM knockdown larvae exhibited sensitivity to excitotoxicity, while augmenting autophagy – both pharmacologically and genetically – alleviated the effects of dATM deficiency. Taken together, the evidence suggests a model in which dATM transduces presynaptic ROS levels, responding to increased ROS by activating the autophagic machinery to induce synaptic growth, while protecting the neuron from excitotoxicity.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):