The fine-tuning of synapse development by oxidative stress and autophagy requires presynaptic ATM kinase
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Two processes 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 toxic. How this balance is maintained is not fully understood. While ataxia-telangiectasia mutated (ATM) is recognized as a key regulator of the DNA damage response, there is increasing evidence of a neuronal-specific role for this ubiquitous kinase and deficiency causes early-onset neurodegeneration. We report a requirement for presynaptic Drosophila ATM (dATM) in neurodevelopment that is independent of its functions in the DNA damage response. Reduction of presynaptic dATM expression causes hypersensitivity to raised oxidative stress and a failure to induce autophagy which leaves mitochondria in excess in neurons. We demonstrate that presynaptic dATM coordinates autophagy through the conserved ATM-AMPK axis. Similarly to mammalian ATM, neuronal dATM is predominantly cytosolic and forms synaptic foci. dATM also colocalizes with autophagosomes. We propose a model wherein dATM responds to increased reactive oxygen species resulting from heightened neuronal activity by activating autophagy to induce synaptic growth, while protecting the neuron from excitotoxicity and oxidative stress.
