The role of microRNA regulation in a Drosophila model of Huntington disease

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The overall goal of this proposal is to determine the roles played by small non-coding RNAs in Huntington Disease (HD), an incurable neurodegenerative disease and the most common monogenic neuropathology in the developed world. HD manifests as a combination of motor, cognitive and behavioural features which deteriorate the patient's physical and mental abilities, ultimately leading to death. Recent studies in humans (Hoss et al., 2014) have demonstrated that many small non-coding RNAs (microRNAs, miRNAs) show differential expression in HD brains suggesting that miRNAs may be involved in the development of HD pathology or be part of a cellular compensatory mechanism that combats the disease. This project investigates these important and timely questions using a Drosophila model of HD. The work will be focused on two central questions:Q1: What are the molecular mechanisms that trigger miRNA dysregulation in HD?Q2: What are the mechanisms that link HD-related miRNA dysregulation to neural dysfunction?The project will be developed as a novel collaboration between Prof. Claudio Alonso at the University of Sussex and Prof. Gillian Bates, FRS at UCL. The Alonso lab is an international leader in the study of the neural roles of miRNAs in Drosophila and Prof. Bates is a world authority in the molecular cellular biology of HD and an expert in mammalian models of HD. The highly complementary nature of our team puts us in an excellent position to determine the roles played by miRNA regulation in a Drosophila model of HD while keeping close to the context of mammalian models of this disease. The project fits the core remit of the MRC Neuroscience and Mental Health Board on "understanding of the mechanisms of neurodegeneration and disorders of the motor system" and will also contribute to advance current models on the molecular control of "the physiology of the nervous system in health and illness".