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The William Harvey Research Institute - Barts and The London

Professor Paul Chapple

Paul

Professor of Molecular Cell Biology

Centre: Endocrinology

Email: j.p.chapple@qmul.ac.uk
Telephone: +44(0) 20 7882 6242

Profile

ORCID iD: https://orcid.org/0000-0003-1876-1505

Dr Paul Chapple was awarded a PhD by University College London in 1997, this investigated the physiological and evolutionary significance of Hsp70 chaperones in a marine organism. He then worked for eight years as a Postdoctoral Researcher in the laboratory of Professor Michael Cheetham at the UCL Institute of Ophthalmology, where he researched the cell biology of molecular chaperone proteins involved in neurodegeneration and blindness. In 2004 he moved to the KCL Institute of Psychiatry to work with Dr Jean-Marc Gallo on the Alzheimer’s protein Tau. Dr Chapple became a Lecturer at the William Harvey Research Institute (WHRI) in 2006, was promoted to Reader in 2010 and Professor in 2014. He has served as a reviewer and committee member for several grant-giving bodies, including BBSRC and the Society for Endocrinology. Current academic roles include that he is the Co-Centre Lead for the Centre for Endocrinology and the WHRI Director of Graduate Studies.

Research

Group members

PhD students: Lisa Romano, Grace Salbury
Postdoctoral researcher: Dr Tatiana Novoselova
Clinical research fellow: Dr Sam O'Toole, Dr Alex Da Costa

Summary

Cell stress and molecular chaperones in human disease
My research concentrates on understanding the role of cell stress and molecular chaperones in health and disease, with a focus on neuronal and endocrine systems.

It is critical for cell survival that protein homeostasis (proteostasis) is maintained. Molecular chaperones are essential modulators of proteostasis networks, regulating aspects of protein quality control, such as folding and degradation. One of my particular interest is understanding how chaperone systems are specialised in different cell types and organelles.

Ongoing projects include:

J proteins in neurodegenerative disorders
J-domain cochaperones are important for neuronal health. This includes the protein sacsin that is mutated in an early onset ataxia. Loss of sacsin disrupts intermediate filament organisation and mitochondrial function. We hypothesise that sacsin functions as a chaperone for specific clients and are currently identifying these proteins to understand disease mechanism.

Cell biology of Pheochromocytoma
Pheochromocytoma are rare, catecholamine-secreting tumors that may precipitate life-threatening hypertension. We are investigating cellular mechanisms of tumorigenesis in pheochromocytoma with a current focus on hypoxia induced signaling pathways.

Chaperones and environmental modulation of primary cilia function
Primary cilia play a role in the coordination of cellular signaling pathways, with dysfunction associated with genetic syndromes and other disease. We are investigating the requirement for chaperones in cilia function and mechanisms that regulate cilia response to the cellular stress.

G protein-coupled receptor trafficking
GPCRs respond to a wide range of extracellular stimuli and are important drug targets. We are elucidating the chaperones involved in GPCR quality control and identifying strategies to rescue cell surface expression of intracellular retained receptor mutants. This research is relevant to pathologies including monogenic obesity and retinal degeneration.

Key Publications

For a full list of publications click here

  • M.H. Parkinson, A.P. Bartmann, L.M.S. Clayton, S. Nethisinghe, R. Pfundt, J.P. Chapple, M.M. Reilly, H. Manji, N.J. Wood, F. Bremner, P. Giunti, Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay, Brain  (2018).
  • E.J. Duncan, R. Lariviere, T.Y. Bradshaw, F. Longo, N. Sgarioto, M.J. Hayes, L.E.L. Romano, S. Nethisinghe, P. Giunti, M.B. Bruntraeger, H.D. Durham, B. Brais, F. Maltecca, B.J. Gentil, J.P. Chapple, Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin, Hum Mol Genet 26(16) (2017) 3130-3143.
  • T.Y. Bradshaw, L.E. Romano, E.J. Duncan, S. Nethisinghe, R. Abeti, G.J. Michael, P. Giunti, S. Vermeer, J.P. Chapple, A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay, Hum Mol Genet 25(15) (2016) 3232-3244.
  • D. Athanasiou, D. Bevilacqua, M. Aguila, C. McCulley, N. Kanuga, T. Iwawaki, J.P. Chapple, M.E. Cheetham, The co-chaperone and reductase ERdj5 facilitates rod opsin biogenesis and quality control, Hum Mol Genet 23(24) (2014) 6594-606.
  • N.V. Prodromou, C.L. Thompson, D.P. Osborn, K.F. Cogger, R. Ashworth, M.M. Knight, P.L. Beales, J.P. Chapple, Heat shock induces rapid resorption of primary cilia, J Cell Sci 125(Pt 18) (2012) 4297-305.
  • E. Meimaridou, J. Kowalczyk, L. Guasti, C.R. Hughes, F. Wagner, P. Frommolt, P. Nurnberg, N.P. Mann, R. Banerjee, H.N. Saka, J.P. Chapple, J.P. King, A.J. Clark, L.A. Metherell, Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency, Nat Genet 44(7) (2012) 740-2.
  • M. Girard, R. Lariviere, D.A. Parfitt, E.C. Deane, R. Gaudet, N. Nossova, F. Blondeau, G. Prenosil, E.G. Vermeulen, M.R. Duchen, A. Richter, E.A. Shoubridge, K. Gehring, R.A. McKinney, B. Brais, J.P. Chapple*, P.S. McPherson, Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), Proc Natl Acad Sci U S A 109(5) (2012) 1661-6. *corresponding
  • D. Athanasiou, M. Kosmaoglou, N. Kanuga, S.S. Novoselov, A.W. Paton, J.C. Paton, J.P. Chapple, M.E. Cheetham, BiP prevents rod opsin aggregation, Mol Biol Cell 23(18) (2012) 3522-31.
  • E. Meimaridou, S.B. Gooljar, N. Ramnarace, L. Anthonypillai, A.J. Clark, J.P. Chapple, The cytosolic chaperone Hsc70 promotes traffic to the cell surface of intracellular retained melanocortin-4 receptor mutants, Mol Endocrinol 25(9) (2011) 1650-60.
  • D.A. Parfitt, G.J. Michael, E.G. Vermeulen, N.V. Prodromou, T.R. Webb, J.M. Gallo, M.E. Cheetham, W.S. Nicoll, G.L. Blatch, J.P. Chapple, The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1, Hum Mol Genet 18(9) (2009) 1556-65.

Collaborators

Internal


External

  • Professor Martin Knight (School of Engineering and Materials Science, QMUL)
    Professor Mike Cheetham (UCL Institute of Ophthalmology)
  • Dr Konstantinos Thalassinos (UCL Institute of Structural and Molecular Biology)
  • Dr Paola Giunti (UCL Institute of Neurology)
  • Dr Bernard Brais and Dr Benoit Gentil (Montreal Neurological Institute and Hospital, McGill University Montreal)
  • Francesca Maltecca (Università Vita-Salute San Raffaele, Milan)

News

September 2017
PhD student Lisa Romano wins a highly commended for her poster presentation on ARSACS at the 2nd International Ataxia Research Conference in Pisa, Italy.

July 2017
BBSRC funding awarded for a three-year project to investigate the role of a molecular chaperone Molecular chaperones in the regulation of the intermediate filament cytoskeleton.

June 2017
ARSACS Foundation funded-scientists at Queen Mary University of London, McGill University and Università Vita-Salute San Raffaele have just published a research paper in the journal Human Molecular Genetics. This work describes the cytoskeleton in cells cultured from ARSACS patients. The cytoskeleton is a dynamic network of filaments that pervades the cytoplasm of cells. It acts to regulate cellular shape and internal organisation, while providing the mechanical support that enables cells to divide and move. The researchers have discovered that one component of the cytoskeleton, known as intermediate filaments, has a dramatically altered organisation in skin cells from ARSACS patients. This in turn impacts on the internal organisation of these cells, as well as the machinery they uses to deal with damaged and unwanted components. This research increases knowledge of what may go wrong at the cellular level in ARSACS.

Professor Paul Chapple (lead researcher for this paper) said “We have identified a cytoskeletal phenotype in skin cells from ARSACS patients. This is important as it should be possible to use this cellular phenotype as a readout in assays to screen for drugs that could have potential therapeutic benefit for ARSACS”.