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

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.

Intracellular transport is driven by kinesin and dynein motors for long-range delivery along microtubules, whereas myosin motors move cargo over short distances along actin tracks, regulate plasma membrane dynamics through the actin cortex and provide flexible tethering of intracellular compartments to the actin cytoskeleton. The human genome has 39 myosin genes, which fall into 12 distinct structural families and in this programme grant we will focus on two classes of myosin motors, myosins of class I and class VI, MYO1F and MYO1G as well as MYO6.
The principal aim of this research programme is to (1) identify the mechanisms involved in regulation of motor activity and cargo attachment, (2) characterise the cellular roles of MYO6-cargo adaptor complexes and (3) elucidate the function of MYO1F and G in microglia. We will investigate the mechanisms that control motor activity and cargo attachment to understand how cargo recognition, transport or tethering and finally motor-cargo uncoupling are temporally and spatially regulated within different tissues and cells. Together with our collaborators we will use biophysical and biochemical approaches to analyse motor properties in vitro. In addition we will take an integrated approach including functional studies, proteomic analysis and high resolution imaging in a range of primary cell types to investigate the specialised cellular functions and pathways that involve MYO6, MYO1F and MYO1G.
This programme will generate fundamental insights into the cellular roles and regulation of myosin motors and their cargo adaptors in mammalian cells. We will investigate how defects in motor function are linked to neurodegeneration, which will provide new information on the underlying mechanisms in neuroinflammation and AD disease progression. In addition this work will offer novel insights for drug-discovery programs, as myosin motors are attractive drug targets.

Who will benefit from this research?
In addition to the specific academic beneficiaries that have been listed in the section above, the public and wider academic community will benefit from our greater understanding of crucial processes in basic cell biology and motor protein function. Of particular importance and interest for the general public is the increase in knowledge about neurological diseases such as dementia. Brain disorders and neurodegeneration affect a high percentage of our ageing population in the UK and place a heavy burden on our health budget. Therefore the outcome from our work will be of interest to a wide range of health professionals. Myosin motor proteins have been shown to be drug targets and we are currently testing new small molecule compounds designed to target specific classes of myosins in our cellular assay systems. Thus sectors of the pharmaceutical industry that develop drugs to treat neurological disorders will be interested in new discoveries and knowledge generated by this work. In the long term patients suffering from neurodegeneration may also benefit and thus there may be a crucial positive impact on improving health, well-being and wealth in the UK. In addition, this research will improve our knowledge about how myosin motor proteins (especially motors like MYO6 and MYO1F) function and therefore will have an impact on industries in the bionanotechnology field. It should be emphasized again that MYO6 is unique, since it moves along actin filaments in the reverse direction to all other motors.
How might they benefit from this research?
1. Health care professionals and patients will benefit from the work undertaken in this study. Although this proposal focuses on the role of a myosin motor protein involved in neurodegeneration, mutations in this motor have also been linked to inherited forms of deafness as well as heart disease and prostate cancer. As mentioned above the social and healthcare costs of these diseases are enormous and therefore any advances in understanding the underlying mechanisms will impact on the treatment of these diseases and the development of disease specific drugs. This will impact on the well-being and quality of life of patients and their immediate social environment. This can create economic benefits by saving health care costs, and will also boost the UK-based pharmaceutical industry.
2. Benefits for Industry: The basic research outlined in this proposal is likely to have a direct impact upon future strategies for treatment. It may directly lead to identification of potential new drug targets for the treatment of neurodegenerative disorders such as motor neuron disease and Alzheimer's disease. Myosin motor proteins have been proven to be excellent drug targets and therefore to establish whether a myosin motor is involved in neuroinflammation is an important step forward in identifying therapeutic targets. We have close collaborations with Biophysicists and Chemists and are currently testing new small molecules for regulating myosin motor activity.
3. The General Public will benefit from this research, because it will help our understanding of the causes of disease and will therefore clearly demonstrate the benefits of basic research to the wider general public.