Position

Senior Lecturer

Areas of Expertise

Parkinson's disease, GABA-A receptor clustering, Glycinergic synapses, Hyperekplexia, Molecular biology, Cell biology (neuronal cell culture, transfection, immunocytochemistry), Confocal microscopy and Proteomics.

Biography

Dr Kirsten Harvey was awarded her Ph.D. in 2000 for a thesis entitled 'MCP-1 gene expression and Langerhans cell/Macrophage distribution in human papilloma virus (HPV) infected cervix uteri lesions' which was performed at the University Hospital Hamburg (Germany) under the supervision of Professor T. Löning. From 1999-2002, she studied glycine receptors containing the alpha3 subunit in the laboratory of Dr Robert J. Harvey at the School of Pharmacy (London), moving on to another project studying glycine receptors and Parkinson's disease from 2003-2005. During this time, she was awarded the title of Honorary Lecturer. In February 2005, Dr Kirsten Harvey was appointed as a Lecturer at The School of Pharmacy and promoted to Senior Lecturer in February 2008.

Research Interests

Parkinson's disease associated proteins LRRK2, PINK1 and DJ-1 (funded by The Wellcome Trust, The British Medical Association, The Royal Society and two School of Pharmacy Ph.D. studentships)

Parkinson's disease (PD) is a common progressive neurodegenerative disorder resulting in tremors, rigidity, akinesia and postural instability. Although the majority of PD cases are idiopathic, the identification of disease-causing mutations in the genes for alpha-synuclein (PARK1), the E3 ubiquitin-protein ligase Parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7) and LRRK2 (PARK8) have suggested molecular mechanisms involved in neuronal death. In Dr Harvey’s laboratory protein kinases and interactors involved in Parkinson’s disease are studied (Plun-Favreau et al. 2007, Nature Cell Biology 9: 1243-1252; Greggio et al 2006, Neurobiology of Disease 23: 329-341; Valente et al 2004, Science 304: 1158-1160). Cell biological and proteomic techniques are used in an effort to i) discover how pathogenic mutations in the cognate genes lead to neuronal death, and ii) to uncover new leads for genetic analysis.

A particular interest lies in the analysis of LRRK2 interacting proteins. Mutations in the PARK8 gene, encoding LRRK2, are the most frequent known cause of PD. LRRK2 is a multidomain protein characterised by intrinsic GTPase and kinase activity. The modification of LRRK2 GTPase and kinase activity by familial PD mutations in the Roc, COR and kinase domains is believed to lead to neuronal cell death but the pathways involved remain elusive. We identified dishevelled (DVL) family proteins (DVL1-3) as LRRK2 interactors. Importantly, DVL proteins have been shown to mediate wingless (Wnt) signalling pathways, leading to multiple downstream effects important for neuronal development and maintenance. Interestingly, co-expression of DVL and LRRK2 in mammalian cellular models resulted in a redistribution of  LRRK2 to cytoplasmic DVL aggregates and familial PD mutations modulate the LRRK2-DVL interaction. Key external collaborators in the PD field include Dr Mark Cookson (National Institute on Aging, NIH, Bethesda, USA), Dr Ann Kingsbury (Queen Square Brain Bank and Institute of Neurology, London) and Drs David Dexter and Kirstin Goldring (UK PDS Tissue Bank, Imperial College, London).

Trapping and accumulation of inhibitory receptors at synapses (funded by a MRC New Investigator Award, a Ph.D. studentship from the Department of Pharmacology and a MRC-Ph.D. studentship): Inhibitory GABA_A and glycine receptors are clustered at synapses via key interactions between the receptors, a 'scaffolding' protein known as gephyrin and an 'exchange factor' called collybistin. Using a multidisciplinary approach, the binding sites for the glycine receptor beta subunit and collybistin was mapped to the C-terminal 'MoeA homology domain' of gephyrin, and mutants of collybistin were shown to prevent gephyrin and associated GABA_A and glycine receptors from being correctly located to synapses (Harvey et al 2004, Journal of Neuroscience 24: 5816-5826). The importance of collybistin for synaptic function was further defined by work in collaboration with Prof Heinrich Betz (Max-Planck-Institute for Brain Research, Frankfurt, Germany) that produced a knockout mouse line missing the collybistin protein (Papadopoulos et al 2007, EMBO Journal 26: 3888-3899) and work on a balanced chromosomal translocation disrupting the human collybistin gene in collaboration with Dr Vera Kalscheuer (Max-Planck Institute for Molecular Genetics, Berlin, Germany; Kalscheuer et al. 2009, Human Mutation, 30: 61-68). A major challenge for the future is to work out how gephyrin clusters GABA_A receptors. These questions are addressed using a multidisciplinary approach, including functional expression of fluorescent protein tagged GABA_A receptor complexes in cell lines, transfection of wild-type and dominant-negative tagged constructs into cultured neurones and custom proteomic screens for GABA_A receptor and gephyrin interactors. Key external collaborators in the GABA_A field include Professor Stephen Moss (Tufts University, MA, USA), Professor Jean-Marc Fritschy (Institute of Pharmacology and Toxicology, University of Zurich, Switzerland) and Dr Verena Tretter (Medical University Vienna, Vienna, Austria).

Human genetics and structure/function studies of glycinergic synapses (funded by the Medical Research Council): In humans, defects in glycinergic neurotransmission result in hyperekplexia, a neurological disorder characterized by an excessive startle response. Hyperekplexia is a risk factor for sudden infant death, due to developmentally-specific breath holding episodes, caused by seizures, and is typically caused by missense and nonsense mutations in GLRA1, which encodes the 'adult' GlyR & alpha 1 subunit. However, many additional cases of hyperekplexia have been reported where no mutations have been found in GLRA1. Using an approach based on biological plausibility, we have uncovered several additional hyperekplexia genes including gephyrin (GPHN; Rees et al 2003, Journal of Biological Chemistry 278: 24688-24696) and RhoGEF collybistin (ARHGEF9; Harvey et al 2004, Journal of Neuroscience 24: 5816-5826). In a recent collaboration with clinicians in Australia, Canada, the USA and The Netherlands, a second major hyperekplexia gene was discovered (Rees et al 2006, Nature Genetics 38: 801-806). Interestingly, the affected protein is a presynaptic glycine transporter, GlyT2, demonstrating that defects in both presynaptic and postsynaptic function can result in similar clinical symptoms. Future research aims to i) discover novel GlyT2 interacting proteins and assess the corresponding genes as candidates in hyperekplexia; ii) to screen presynaptic GABA transporters in types of idiopathic generalised epilepsy where postsynaptic GABA_A receptor deficits have already been identified. In late 2007, we also characterised a mutation in the bovine GlyT2 gene, causing congenital muscular dystonia type 2 (Charlier et al 2008, Nature Genetics 40: 449-453). Key external collaborators include Professor Mark Rees (University of Swansea) and Dr Stéphane Supplisson (Ecole Normale Supérieure, Paris).

Research Group Members

Postdoctoral Fellows: Eloisa Carta
PhD Students:  Rosa Sancho, Bernard Law, Sarah Ramsden

Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E, Deas E, Venkateswarlu K, Menzel C, Ullmann R, Tommerup N, Dalprà L, Tzschach A, Selicorni A, Lüscher B, Ropers HH, Harvey K, Harvey RJ (2009) A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression and mental retardation. Human Mutation, 30: 61-68.

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: 1243-1252.

Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty S, Graham GE, Armstrong L, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ (2006) Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nature Genetics 38: 801-806.

Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiology of Disease 23: 329-341.

Extended Publications