Linking the DNA damage response to synapse development and plasticity

The ATM kinase is master regulator of the DNA damage response (DDR). Deficiency of ATM in ataxia-telangiectasia leads to cerebellar ataxia and neurodegeneration but the reason why cerebellar neurons are particularly vulnerable to loss of ATM is not fully known. ATM may also be required for the normal development and maturation of synapses with altered neural development potentially underpinning later degeneration. This project will examine roles for ATM in synapse development and plasticity in the fruit fly, Drosophila melanogaster. We will use a combination of genetics, confocal and electrophysiology to examine ATM localisation and function at the neuromuscular junction, which serves as a model for neural development and homeostasis. Disease causing mutations in human ATM will be studied in a naive ATM-deficient Drosophila background to identify different cellular pathways requiring ATM function. Finally, ATM activation and dimerization will be studied in cultured neurons by single-molecule microscopy.