Researchers have discovered how genetic mutations linked to Parkinson's disease might play a key role in the death of brain cells, potentially paving the way for the development of more effective drug treatments.
In the new study, published in Nature Neuroscience, a team of researchers from UCL, the University of Cambridge and the University of Sheffield showed how defects in the Parkinson's gene Fbxo7 cause problems with 'mitaphagy' – an essential process through which our bodies are able to get rid of damaged cells.
Mitochondria are the 'energy powerhouses' of cells. Their function is vital in nerve cells which require a great deal of energy in order to function and survive. Dysfunctional mitochondria are potentially very harmful and, normally, cells dispose of the damaged mitchondria by self-eating them, a process called mitophagy.
Most of what we know about the mitophagy process comes from the study of the familial forms of Parkinson's, one of the most common diseases of the brain. Over the last three years, two genes associated with familial Parkinson's disease, PINK1 and Parkin, have been reported to play a role in mitophagy.
This new study shows just how central the role of mitophagy is and how mutations in Fbxo7 are also linked with the disease and interfere with the PINK1-Parkin pathway. In people with Parkinson's, genetic mutations cause defects in mitophagy, leading to a build-up of dysfunctional mitochondria. This is likely to explain, at least partially, the death of brain cells in Parkinson's patients with these mutations.
One of the lead authors, Dr Helene Plun-Favreau from the UCL Institute of Neurology, said: "These findings suggest that treatment strategies that target mitophagy might be developed to benefit patients with Parkinson's disease in the future."
Dr Plun-Favreau, who was recently awarded a grant from the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, said: "What makes the study so robust is the confirmation of defective mitophagy in a number of different Parkinson's models, including cells of patients who carry a mutation in the Fbxo7 gene."
Co-author Dr Heike Laman, University of Cambridge, said: "This research focuses the attention of the PD community on the importance of the proper maintenance of mitochondria for the health of neurons. We are really only at the very beginning of this work, but perhaps we can use this information to enable earlier diagnosis for Parkinson's disease patients or design therapies aimed at supporting mitochondrial health."
Professor Nicholas Wood, Neuroscience programme director for the NIHR University College London Hospitals BRC, said: "It is very exciting to see how detailed biological work of this type can highlight a single pathway that contributes to Parkinson's disease. This presents the opportunity of more rationale drug design for many forms of parkinsonism."
Professor Hugh Perry, chair of the Neurosciences and Mental Health Board at the Medical Research Council who part-funded the study, said: "This study raises interesting questions about precisely how brain cells die in a Parkinson's patient: the process which is key to understanding the disease's progression. The more we understand about the basic molecular events which contribute to the onset and progression of Parkinson's disease, the better placed we will be to develop treatments to stop it in its tracks."
The work was funded by the Medical Research Council, the Wellcome Trust and The NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.
Notes to editors
For more information, contact David Weston in the UCL Press Office on +44 (0) 203 108 3844 (out of hours 07917 271 364) or d.weston@ucl.ac.uk
1. The paper, entitled 'The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy' by Plun-Favreau et al, is published in Nature Neuroscience.
About the Medical Research Council:
Over the past century, the Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers' money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed.
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The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. http://www.wellcome.ac.uk
The NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London was established in 2007 and is at the forefront of research into some of the major causes of illness and disease-related death. The biomedical research centre (BRC), which has invested over £100m in new experimental medicine research projects, staff, equipment and facilities, was last year awarded a further £98million in government funding from the National Institute for Health Research. The BRC focuses on a range of advances in medical research that will have a direct impact on patients' care and quality of life, and will also save many lives. These include advances in the areas of cancer, cardiovascular disease, infectious disease, women's health, oral health and neurological diseases such as epilepsy, stroke and multiple sclerosis.
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Journal
Nature Neuroscience