Chapple, Paul

Paul Chapple

Professor of Molecular Cell Biology

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 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 in 2006, was promoted to Reader in 2010 and Professor in 2014. He serves as a reviewer and committee member for grant-giving bodies, including current membership of BBSRC Committee D and previous membership of the Society for Endocrinology Science Committee.

Summary of Research

Cell stress and molecular chaperones in human disease

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. My research asks the question how are chaperone systems specialised in different cell types and organelles. The focus is on understanding the consequences and cellular mechanisms of chaperone function in human disease. Ongoing projects include:

  1. 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.

  2. Cell biology of Pheochromocytoma:
    Pheochromocytoma are rare, catecholamine-secreting tumor that may precipitate life-threatening hypertension. We are investigation cellular mechanisms of tumorigenesis in pheochromocytoma with a current focus hypoxia induced signalling pathways.

  3. Chaperones and environmental modulation of primary cilia function:
    Primary cilia play a role in the coordination of cellular signalling 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.

  4. 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.

Academic Responsibilities

Co-Centre Lead, Centre for Endocrinology
WHRI Director of Graduate Studies
Lecturer for MB BS, PgDip/Msc Endocrinology, BMedSci Molecular Medicine/Molecular Therapeutic, BSc Neuroscience.

Mitochondrial networks in human fibroblasts (left) and primary cilia in kidney cells (right).

Members of the Group

PhD students: Lisa Romano
Postdoctoral researcher: Dr Teisha Bradshaw
Clinical research fellow: Dr Sam O'Toole

Key Publications

For a full list of publist publications click here
 

Bradshaw, TY, Romano, LE, Duncan, EJ, Nethisinghe, S, Abeti, R, Michael, GJ, Giunti, P, Vermeer, S, and Chapple, JP (2016). A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay. Hum Mol Genet.

Dalbay, MT, Thorpe, SD, Connelly, JT, Chapple, JP, and Knight, MM (2015). Adipogenic Differentiation of hMSCs is Mediated by Recruitment of IGF-1r Onto the Primary Cilium Associated With Cilia Elongation. Stem Cells Vol. 33, 1952-1961.

Prodromou NV, Thompson CL, Osborn DP, Cogger KF, Ashworth R, Knight MM, Beales PL, Chapple JP (2012). Heat shock induces rapid resorption of primary cilia. J Cell Sci Vol.125, (Pt 18) 4297-4305. 10.1242/jcs.100545

Girard M, Lariviere R, Parfitt DA, Deane EC, Gaudet R, Nossova N, Blondeau F, Prenosil G, Vermeulen EG, Duchen MR, Richter A, Shoubridge EA, Gehring K, McKinney RA, Brais B, Chapple JP, McPherson PS (2012). Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol.109, (5) 0027-8424 1661-1666. 10.1073/pnas.1113166109

Meimaridou E, Gooljar SB, Ramnarace N, Anthonypillai L, Clark AJ, Chapple JP (2011). The cytosolic chaperone Hsc70 promotes traffic to the cell surface of intracellular retained melanocortin-4 receptor mutants. Mol Endocrinol Vol.25, (9) 1650-1660. 10.1210/me.2011-1020

Parfitt DA, Michael GJ, Vermeulen EG, Prodromou NV, Webb TR, Gallo JM, Cheetham ME, Nicoll WS, Blatch GL, Chapple JP (2009). The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Hum Mol Genet Vol.18, (9) 1556-1565. 10.1093/hmg/ddp067

Chapple JP, Gallo JM, Cooper TA, Gallo JM (2007). Expression, localization and Tau Exon 10 splicing activity of the brain RNA-binding protein TNRC4. Human Molecular Genetics Vol.16, (22) 2760-2769. 10.1093/hmg/ddm233

Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL (2005). Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nature Genetics Vol.37, (10) 1061-4036 1135-1140. 10.1038/ng1644

Westhoff B, Chapple JP, van der Spuy J, Höhfeld J, Cheetham ME (2005). HSJ1 Is a Neuronal Shuttling Factor for the Sorting of Chaperone Clients to the Proteasome. Current Biology Vol.15, (11) 0960-9822 1058-1064. 10.1016/j.cub.2005.04.058

Metherell LA, Chapple JP, Cooray S, David A, Becker C, Rüschendorf F, Naville D, Begeot M, Khoo B, Nürnberg P, Huebner A, Cheetham ME, Clark AJ (2005). Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. NAT GENET Vol.37, (2) 1061-4036 166-170. 10.1038/ng1501

Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nürnberg P, Mann NP, Banerjee R, Saka HN, Chapple JP, King PJ, Clark AJ, Metherell LA (2012). Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet Vol.44, (7) 740-742. 10.1038/ng.2299
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