Investigating the role of Myosin VI in quality control of mitochondria linked to Parkinson's disease pathology

A significant proportion of our ageing population is affected by the late onset of neurodegenerative disorders such as Parkinson's, motor neuron or Alzheimer's disease. A better understanding of what causes these neurodegenerative diseases will lead to new therapeutic and preventive strategies.
More and more research now suggests that Parkinson's disease and also other forms of dementia are caused by defects in a cellular pathway that is used to control the quality of mitochondria, our cellular power stations. If this turnover pathway and the replacement of 'old' mitochondria does not function properly, it can cause decreased energy production and the pile up of damaged mitochondria, which eventually in nerve cells causes them to die.
Our research is focused on myosin VI, a molecular motor protein, which drives 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. New results show that this motor protein is recruited to damaged mitochondria and may play a role in their turn over and their quality control.
We thus hope to identify the precise roles of myosin VI and its adaptor proteins in the pathway that is important for clearance of damaged mitochondria. This will open up new areas of research that may guide future clinical studies and the development of potential diagnostic tools and possible therapeutic strategies.

In this project we will investigate the molecular function of the actin-based motor protein myosin VI in mitochondrial quality control. Defects in mitochondrial turnover are closely linked to Parkinson's disease (PD), the second most common neurodegenerative disorder. A hereditary form of PD is caused by mutations in the E3 ubiquitin ligase Parkin; this protein has been shown to mediate selective autophagy of damaged mitochondria, called mitophagy. Several lines of evidence and data from published large-scale whole genome studies suggest a functional link between Parkin and myosin VI and its cargo adaptors. To test this hypothesis and analyse the link between myosin VI and Parkin in more detail we will use in situ proximity labeling and a combination of confocal fluorescence microscopy, live cell and super-resolution microscopy as well as electron microscopy. To determine the requirement of myosin VI and its adaptor proteins for Parkin-mediated mitophagy, we will use siRNA KD cells, KO cells created by CRISPR/Cas9 genome editing, primary fibroblasts and neurons from our myosin VI KO mouse as well as iPS cells generated from human PD patient fibroblasts. In addition we will employ multiple approaches to assess whether loss of myosin VI or its adaptor proteins affects mitophagy and thereby leads to an accumulation of damaged mitochondria with reduced function.

Who will benefit from this research?
In addition to the specific academic beneficiaries that have been listed in the section above, the general public, the pharmaceutical industry, and wider academic and clinical community will benefit from the new knowledge gained on crucial processes in basic cell biology and motor protein function. Of particular importance and interest for the general public will be the increase in knowledge about neurological diseases such as Parkinson's disease. Brain disorders and neurodegeneration affect a high percentage of our aging population in the UK and places a heavy burden on our health system. 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 might be a crucial positive impact on improving health, well-being and wealth in the UK. In addition the outcome from this research will improve our knowledge on myosin motor proteins and therefore have an impact on industries in the bionanotechnology field.
How might they benefit from this research?
1. Health care professionals and patients will benefit from work undertaken in this study. Although this proposal focuses on the role of 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 our understanding of 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, but also will provide a boost to the UK-based pharmaceutical industry.
2. Benefits for the Industry: The basic research outlined in this proposal is likely to have a direct impact upon future strategies for treatment. It might directly lead to identification of potential new drug targets for the treatment of neurodegenerative disorders such as motor neuron disease, Alzheimer's and Parkinson's disease. Myosin motor proteins have been proven to be excellent drug targets and therefore to establish whether a myosin motor is involved in autophagy and the clearance of damaged mitochondria to prevent neuronal cell death 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 therefore demonstrate the benefits of basic research to the wider society.