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Dr Helene Plun-Favreau
Fax:0207 278 5616
Appointments:Senior Lecturer, Molecular Neuroscience, Institute of Neurology
Parkinson's disease (PD) is a common, disabling, incurable neurodegenerative disease. Our knowledge of the molecular events leading to PD is being greatly enhanced by the study of relatively rare familial forms of the disease. Nevertheless, the pathways leading from the genetic mutations to nigral cell degeneration and the other features in PD remain poorly understood. In particular, it is unclear whether one is looking at a range of pathways acting independently and in parallel or whether there is some convergence of the pathways with the tempting reward of a single final common pathway.
Mutations in PINK1, a putative mitochondrial protein kinase, are associated with the PARK6 autosomal recessive, early-onset PD susceptibility locus1. Moreover, point mutations in HtrA2 have recently been identified as a susceptibility factor for PD (PARK13)2. We recently showed that HtrA2 interacts with PINK1 and both are components of the same stress-sensing pathway. Importantly, HtrA2 phosphorylation is decreased in the brains of PD patients carrying PINK1 mutations. We suggested that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to increased resistance of cells to mitochondrial stress.
The focus of our lab is to further dissect the molecular pathways which lead to PD as well as to try and identify new components in these pathways. To do this we have chosen a range of biochemical, molecular biological and cellular techniques to provide a list of new proteins which may play a role in PD. We aim to assess how these proteins talk to each other and how important this crosstalk is in the development of the disease. To this end we have access to human brain tissue as well as to mice in which HtrA2 and PINK1 genes have been disrupted.
Despite the major progress in the field, available treatments for PD are palliative in nature, relieving the symptoms but only postponing mortality. A cure for PD is, therefore, of great importance. A major hindrance in these studies has been the absence of a relevant cellular model for human disease in the brain. The development of a human neural cell model, using dopaminergic (DA) cells on a genetic background identical to that found in patients carrying PD mutations, will provide a unique experimental system far closer to the disease state which we aim to use to examine the impact of PD mutations on the cell biology and biochemistry of cellular death in this disorder. Therefore, we wish to take advantage of major advances in the field of stem cell technology to reprogram fibroblasts from patients carrying mutations in PD-linked genes (as well as age matched controls) into a stem cell like state and thence into DA neurons (collaboration with Dr P Lewis and Pr J Hardy, UCL). This will allow us to pursue our cell biology, biochemistry and signaling studies in cells which are karyotypically identical to those which are dying within the brains of patients with PD-linked gene mutations.
If we can indeed discover more of the pathway to cell dysfunction and death, then this in turn provides more options for therapeutic intervention for PD.
1. 1. Valente et al., Science 2004 May; 304(5674): 1158-60
2. 2. Strauss et al., Hum. Mol. Genet. 2005 Aug; 14(15): 2099-111
3. 3. Plun-Favreau et al., Nat. Cell. Biol. 2007 Nov (11): 1243-1252
- Identification of new components in Parkinson's Disease signalling pathways
- Neurological disease
Displaying 30 most recent publications. For the full list please visit UCL Discovery
- Burchell VS,Nelson DE,Sanchez-Martinez A,Delgado-Camprubi M,Ivatt RM,Pogson JH,Randle SJ,Wray S,Lewis PA,Houlden H,Abramov AY,Hardy J,Wood NW,Whitworth AJ,Laman H,Plun-Favreau H (2013) The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci. 10.1038/nn.3489.
- Bartolome F,Wu HC,Burchell VS,Preza E,Wray S,Mahoney CJ,Fox NC,Calvo A,Canosa A,Moglia C,Mandrioli J,Chiò A,Orrell RW,Houlden H,Hardy J,Abramov AY,Plun-Favreau H (2013) Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron, 78(1), 57 - 64. 10.1016/j.neuron.2013.02.028.
- Manzoni C,Mamais A,Dihanich S,Abeti R,Soutar MP,Plun-Favreau H,Giunti P,Tooze S,Bandopadhyay R,Lewis PA (2013) Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta. 10.1016/j.bbamcr.2013.07.020.
- Plun-Favreau H,Burchell VS,Holmström KM,Yao Z,Deas E,Cain K,Fedele V,Moisoi N,Campanella M,Miguel Martins L,Wood NW,Gourine AV,Abramov AY (2012) HtrA2 deficiency causes mitochondrial uncoupling through the F₁F₀-ATP synthase and consequent ATP depletion. Cell Death Dis, 3, e335. 10.1038/cddis.2012.77.
- Fitzgerald JC,Camprubi MD,Dunn L,Wu HC,Ip NY,Kruger R,Martins LM,Wood NW,Plun-Favreau H (2012) Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function. Cell Death Differ, 19(2), 257 - 266. 10.1038/cdd.2011.90.
- Yao Z,Gandhi S,Burchell VS,Plun-Favreau H,Wood NW,Abramov AY (2011) Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease. J Cell Sci, 124(Pt 24), 4194 - 4202. 10.1242/jcs.088260.
- Devine MJ,Plun-Favreau H,Wood NW (2011) Parkinson's disease and cancer: two wars, one front. Nat Rev Cancer, 11(11), 812 - 823. 10.1038/nrc3150.
- Deas E,Wood NW,Plun-Favreau H (2011) Mitophagy and Parkinson's disease: the PINK1-parkin link. Biochim Biophys Acta, 1813(4), 623 - 633. 10.1016/j.bbamcr.2010.08.007.
- Deas E,Plun-Favreau H,Gandhi S,Desmond H,Kjaer S,Loh SH,Renton AE,Harvey RJ,Whitworth AJ,Martins LM,Abramov AY,Wood NW (2011) PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet, 20(5), 867 - 879. 10.1093/hmg/ddq526.
- Plun-Favreau H,Lewis PA,Hardy J,Martins LM,Wood NW (2010) Cancer and Neurodegeneration: Between the Devil and the Deep Blue Sea PLOS GENET, 6(12). 10.1371/journal.pgen.1001257.
- Burchell VS,Gandhi S,Deas E,Wood NW,Abramov AY,Plun-Favreau H (2010) Targeting mitochondrial dysfunction in neurodegenerative disease: Part II. Expert Opin Ther Targets, 14(5), 497 - 511. 10.1517/14728221003730434.
- Burchell VS,Gandhi S,Deas E,Wood NW,Abramov AY,Plun-Favreau H (2010) Targeting mitochondrial dysfunction in neurodegenerative disease: Part I. Expert Opin Ther Targets, 14(4), 369 - 385. 10.1517/14728221003652489.
- Yao Z,Gandhi S,Plun-Favreau H,Wood NW,Abramov AY (2010) PINK1 Deficiency and Mitochondrial Dysfunction in Neurons and Skeletal Myocytes BIOPHYSICAL JOURNAL, 98(3), 381A - 381A.
- Moisoi N,Klupsch K,Fedele V,East P,Sharma S,Renton A,Plun-Favreau H,Edwards RE,Teismann P,Esposti MD,Morrison AD,Wood NW,Downward J,Martins LM (2009) Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response Cell Death and Differentiation, 16(3), 449 - 464. 10.1038/cdd.2008.166.
- Deas E,Plun-Favreau H,Wood NW (2009) PINK1 function in health and disease. EMBO Mol Med, 1(3), 152 - 165. 10.1002/emmm.200900024.
- Tain LS,Chowdhury RB,Tao RN,Plun-Favreau H,Moisoi N,Martins LM,Downward J,Whitworth AJ,Tapon N (2009) Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin Cell Death and Differentiation, 16(8), 1118 - 1125. 10.1038/cdd.2009.23.
- Gandhi S,Wood-Kaczmar A,Yao Z,Plun-Favreau H,Deas E,Klupsch K,Downward J,Latchman DS,Tabrizi SJ,Wood NW,Duchen MR,Abramov AY (2009) PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death Molecular Cell, 33(5), 627 - 638. 10.1016/j.molcel.2009.02.013.
- Plun-Favreau H,Gandhi S,Wood-Kaczmar A,Deas E,Yao Z,Wood NW (2008) What have PINK1 and HtrA2 genes told us about the role of mitochondria in Parkinson's disease? Annals of the New York Academy of Sciences, 1147, 30 - 36. 10.1196/annals.1427.032.
- Fitzgerald JC,Plun-Favreau H (2008) Emerging pathways in genetic Parkinson's disease: autosomal-recessive genes in Parkinson's disease--a common pathway? The FEBS Journal, 275(23), 5758 - 5766. 10.1111/j.1742-4658.2008.06708.x.
- Plun-Favreau H,Hardy J (2008) PINK1 in mitochondrial function. Proceedings of the National Academy of Sciences of the United States of America, 105(32), 11041 - 11042. 10.1073/pnas.0805908105.
- Plun-Favreau H,Klupsch K,Moisoi N,Gandhi S,Kjaer S,Frith D,Harvey K,Deas E,Harvey RJ,McDonald N,Wood NW,Martins LM,Downward J (2007) The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nature Cell Biology, 9(11), 1243 - 1252. 10.1038/ncb1644.
- Strauss KM,Martins LM,Plun-Favreau H,Marx FP,Kautzmann S,Berg D,Gasser T,Wszolek Z,Müller T,Bornemann A,Wolburg H,Downward J,Riess O,Schulz JB,Krüger R (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet, 14(15), 2099 - 2111. 10.1093/hmg/ddi215.
- Strauss KM,Martins LM,Plun-Favreau H,Marx FP,Kautzmann S,Berg D,Gasser T,Wszolek Z,Müller T,Bornemann A,Wolburg H,Downward J,Riess O,Schulz JB,Krüger R (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Human Molecular Genetics, 15(14), 2099 - 2111.
- Perret D,Guillet C,Elson G,Froger J,Plun-Favreau H,Rousseau F,Chabbert M,Gauchat JF,Gascan H (2004) Two different contact sites are recruited by cardiotrophin-like cytokine (CLC) to generate the CLC/CLF and CLC/sCNTFRalpha composite cytokines. Journal of Biological Chemistry, 279(42), 43961 - 43970.
- Plun-Favreau H,Perret D,Diveu C,Froger J,Chevalier S,Lelièvre E,Gascan H,Chabbert M (2003) Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor. Journal of Biological Chemistry, 278(29), 27169 - 27179.
- Lisbonne M,Plun-Favreau H (2002) French Society of Immunology: Cytokine Meeting May 16-17, 2002, Le Croisic, Port-aux-Rocs, France. Eur Cytokine Netw, 13(4), 474 - 476.
- Guillet C,Lelièvre E,Plun-Favreau H,Froger J,Chabbert M,Hermann J,Benoit de Coignac A,Bonnefoy JY,Gascan H,Gauchat JF,Elson G (2002) Functionally active fusion protein of the novel composite cytokine CLC/soluble CNTF receptor. European Journal of Biochemistry, 269(7), 1932 - 1941.
- Lelièvre E,Plun-Favreau H,Chevalier S,Froger J,Guillet C,Elson GC,Gauchat JF,Gascan H (2001) Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine: specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor alpha component. Journal of Biological Chemistry, 276(25), 22476 - 22484.
- Plun-Favreau H,Elson G,Chabbert M,Froger J,de Lapeyrière O,Lelièvre E,Guillet C,Hermann J,Gauchat JF,Gascan H,Chevalier S (2001) The ciliary neurotrophic factor receptor alpha component induces the secretion of and is required for functional responses to cardiotrophin-like cytokine. The EMBO Journal, 20(7), 1692 - 1703.
- Elson GC,Lelièvre E,Guillet C,Chevalier S,Plun-Favreau H,Froger J,Suard I,de Coignac AB,Delneste Y,Bonnefoy JY,Gauchat JF,Gascan H (2000) CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nature Neuroscience, 3(9), 867 - 872.
- 2002: Doctor of Philosophy, Universite d'Angers
- 1999: Master of Science, Universite de Poitiers
- 1998: Bachelor of Science, Universite d'Angers
- 2D Difference Gel Electrophoresis
- Cell culture
- Confocal microscopy
- ES cell manipulations
- Enzyme assays
- Gene expression
- Genomic analyses
- In vivo models
- Mitochondrial function
- Models of disease
- Neural signalling
- Neural stem cells
- Neurodegenerative diseases
- Non-viral vectors
- Parkinson's disease
- Parkinson's disease
- Protein purification
- Protein transport/localisation
- RNA interference
- Recombinant protein expression
- Signalling in Parkinson's Disease
- Stem cells
- Transgenic mice
- Viral vectors
- Western blotting