Research led by consortium researchers Dr Helene Plun-Favreau (UCL Institute of Neurology) and Dr Alex Whitworth (University of Sheffield), and collaborator Dr Heike Laman (University of Cambridge), has 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, the team
cross-institutional researchers showed how defects in the Parkinson’s gene
Fbxo7 cause problems with mitophagy.
Mitophagy is an essential process
through which our bodies are able to get rid of
damaged, and therefore potentially very harmful, mitochondria (‘energy
function is vital in nerve cells). 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. Furthermore, these findings suggest that treatment strategies that target
mitophagy might be developed to benefit patients with Parkinson's disease in
Helene 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, Parkinson's UK, and the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.
Burchell, V.S., Nelson, D.E., Sanchez-Martinez, A., Delgado-Camprubi, M., Ivatt, R.M., Pogson, J.H., Randle, S.J., Wray, S., Lewis, P.A., Houlden, H., Abramov, A.Y., Hardy, J., Wood, N.W., Whitworth, A.J., Laman, H., Plun-Favreau, H., 2013. The Parkinson’s disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci advance online publication.