Spatial and temporal mechanisms controlling diverse myosin motor functions in health and disease

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A significant proportion of our ageing population is affected by the late onset of neurodegenerative disorders such as motor neuron or Alzheimer's disease. A better understanding of what causes these neurodegenerative diseases will lead to new therapeutic and preventive strategies. Our research is focused on small nanoscale molecular motor proteins that drive cargo along tracks to specific sites in the cell, rather like a train running along a railway network to its specific destinations. The cargo is hooked up to this motor with the help of specific adaptor proteins that we have previously identified in our research. It is important to understand how these molecular machines are controlled and regulated, since defects in these myosin motors can cause different forms of dementia. The first aim of our research is to investigate a new on/off switch that we believe may trigger the motor to start moving to its destinations in the cell. Furthermore, we will determine how the specific cargo molecules are attached to the motor and how the cargo is uncoupled from the motor at the end of the journey. In a second project we will analyse the specific function of MYO6, an unusual myosin motor with a reverse gear, and one of its cargo adaptor proteins in astrocytes, which are a specific type of glia cell in the brain. Glia cells have many functions in the brain; they protect and support nerve cells and clear the brain of dead cells by a process called phagocytosis. We will determine whether the absence of MYO6 causes defects in clearance of debris from the brain.In a third project we will investigate why, in Alzheimer's disease, specific immune cells in the brain called microglia have more of another myosin, called MYO1F. In these patients, the microglia become 'hyperactive' and the brain becomes inflamed. We will investigate whether increased MYO1F contributes to the inflammation of the brain, and whether we can inhibit the inflammation by turning off this myosin. Myosin motors are druggable targets and a few inhibitors are already available for different classes of myosins. Thus we believe that our research will open up new areas that will guide future clinical studies and the development of potential diagnostic tools and possible therapeutic strategies.