Plun-Favreau Laboratory – Mitophagy and neurodegeneration
Dr Helene Plun-Favreau
Helene Plun-Favreau is a Senior lecturer and a cell biologist by training.
After a PhD in France (Angers University) in signal transduction, Helene did her postdoctoral work with Professor Julian Downward at CRUK. The discoveries and work she did in this area led her towards neurodegeneration and she was successful in being appointed to an MRC Career Development Fellowship to work in the Department of Molecular Neuroscience at UCL Institute of Neurology. Since her arrival in 2007 Helene has carried out some significant work on the molecular pathways associated with mitophagy and other mitochondrial dysfunctions in neurodegenerative disorders. The approaches they have undertaken require live cell microscopy and complex molecular and cellular biology, and provide a more complete picture of the pathways that play a role in the pathogenesis of neurodegeneration.
In recent years, it has become clear that even in clinically distinct neurodegenerative conditions, there are common underlying themes in how the neurons become sick and die. One such theme is a breakdown in the maintenance of mitochondria, which plays a central role in Parkinson’s disease and in other neurodegenerative conditions.
Mitochondria are the ‘energy powerhouses’ of cells. Their function is vital in long-lived neurons, where mitochondria must be maintained for an entire lifetime, and where a great deal of energy is required for them to function and survive.
The selective autophagy of damaged mitochondria (mitophagy) is critical for cell survival as it maintains optimal cellular energy production whilst avoiding the toxic accumulation of damaged mitochondria. Important information about the control of mitophagy has come from the study of the genes associated with autosomal recessive Parkinson’s disease. Of particular interest, PINK1 (mitochondrial kinase) and Parkin (E3-ubiquitin ligase) have been found to play crucial roles in mitophagy.
Against this background, our lab focuses on the following themes:
- Understanding further the mitophagy process
- Identifying the major molecular players in PINK1-induced mitophagy.
- Unravelling the upstream pathways that regulate the mitophagy process.
- Assessing mitophagy and other mitochondrial dysfunctions in iPSC-derived neurons from patients with Parkinson’s disease, and with other neurodegenerative diseases (E.g Alzheimer’s disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, mitochondrial DNA disease etc).
Our ultimate goal is to identify compounds that are able to modulate mitophagy and rescue mitochondrial pathophysiology and neuronal death.
10 selected publications
• Delgado-Campubri, M., Esteras, N., Soutar, M.P., Plun-Favreau, H*., Abramov, A.Y*. Cell Death Differ. (2016). *co-last authorship
• Berezhnov, A.V., Soutar, M.P., Fedotoca, E.I, Frolova, M.S., Plun-Favreau, H., Zinchenko, V. P., Abramov, A.Y. J Biol Chem., 289(21):14569-82 (2016).
• Birsa, N., Norkett, R., Wauer, T., Mevissen, T.E., Wu, H. C., Foltynie, T., Bhatia, K., Hirst, W. D., Komander, D., Plun-Favreau, H., Kittler, J. T. J Biol Chem., (2014).
• Tufi, R., Gandhi, S., de Castro, I. P., Lehmann, S., Angelova, P. R., Dinsdale, D., Deas, E., Plun-Favreau, H., Nicotera, P., Abramov, A. Y., Willis, A. E., Mallucci, G. R., Loh, S. H. Y., Martins L. M. Nat Cell Biol., 16(2):157-66 (2014).
• Burchell, V. S., Nelson, D. E., Sanchez-Martinez, A., Delgado-Camprubi, M., Wray, S., Lewis, P. A., Houlden, H., Abramov, A. Y., Hardy, J., Whitworth, A. J., Wood, N. W., Laman, H., Plun-Favreau, H. Nat. Neurosci., 16, 1257-1265 (2013).
• Bartolome, F., Burchell, V. S., Prezza, E., Wu, H. C., Wray, S., Mahoney, C., Fox, N., Calvo, A., Canosa, A., Moglia, C., Mandrioli, J., Chio, A., Orrell, R. W., Houlden, H., Hardy, J., Abramov, A. Y., Plun-Favreau, H. (2013). Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 10;78(1):57-64.
• Fitzgerald, J. C., Camprubi, M. D., Dunn, L., Wu, H. C., Ip, N. Y., Kruger, R., Martins, L. M., Wood, N. W., Plun-Favreau, H. (2012). Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function. Cell Death Differ 19(2), 257-266.
• Deas, E., Plun-Favreau, H., Gandhi, S., Desmond, H., Kjaer, S., Loh, S. H., Renton, A. E., Harvey, R. J., Whitworth, A. J., Martins, L. M., Abramov, A. Y., Wood, N. W. (2011). PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 20(5), 867-879.
• Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., Downward, J., Latchman, D. S., Tabrizi, S. J., Wood, N. W., Duchen, M. R., Abramov, A. Y. (2009). PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-induced Cell Death. Molecular Cell 33(5), 627-638.
• Plun-Favreau, H., Klupsch, K., Moisoi, N., Gandhi, S., Kjaer, S., Frith, D., Harvey, K., Deas, E., Harvey, R. J., McDonald, N., Wood, N. W., Martins, L. M., Downward, J. (2007). The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nature Cell Biology 9(11), 1243-1252.
Members of the lab
Postdoctoral Research Associate
Dr Marc Soutar (2011-present) is a postdoctoral research associate investigating how kinase signalling/cell metabolism/oxidative stress regulates mitophagy, a process defective in Parkinson’s disease. Marc obtained his PhD in 2010, within the Ninewells Medical School at the University of Dundee, Scotland under the supervision of Dr Calum Sutherland. The work presented in his thesis further characterised upstream kinase signalling pathways in Alzheimer’s disease.
Miss Louise King (2014-present) studied Neuroscience at the University of Leeds before beginning a MRC-funded studentship at the Queen Square Centre for Neuromuscular Diseases. Louise is in her final year of her PhD which involves studying mitophagy in Mitochondrial DNA disease and the effect of mtDNA damage on inducing mitophagy. She is co-supervised by Prof. Michael Hanna.
Dr David Lynch (2014-present) studied medicine in The Royal College of Surgeons in Ireland and underwent post-graduate training in medicine and neurology before beginning a studentship funded by the Leonard Wolfson Experimental Neurology Centre. His research focuses on the genetics and cell biology of hereditary leukodystrophies and Hereditary Spastic Paraplegia. He is co-supervised by Prof. Henry Houlden.
Miss Jasmine Harley (2015-present) is a Biomedical science graduate from Sheffield University. Jasmine is developing a high throughput mitophagy screen in iPSC-derived neurons, with the ultimate aim to find new therapeutic targets for Parkinson's disease.
Mr Liam Kempthorne (2016 – present) recently graduated from the University of Leeds with a BSc in Neuroscience. During his degree he undertook a placement year at the Mayo Clinic’c brain bank in Florida exploring the relationship between microglial phenotype and white matter disease. Liam is currently working in collaboration with the UCL Drug Discovery Institute to develop a drug screen to identify novel modulators of PINK1-dependant mitophagy. Liam is co-supervised by Dr Sonia Gandhi.