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Dr Helene Plun-Favreau
Queen Square
London
WC1N 3BG
Appointment
  • Senior Lecturer
  • Molecular Neuroscience
  • Institute of Neurology
  • Faculty of Brain Sciences
 
 
Research Groups
Research Themes
Research Summary
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
Academic Background
2002 PhD Doctor of Philosophy Universite d'Angers
1999 MSc Master of Science Universite de Poitiers
1998 BSc Bachelor of Science Universite d'Angers
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