Dr Paul Skehel

Dr Paul Skehel
BSc PhD
Senior Lecturer
Hugh Robson Building
George Square
Edinburgh
EH8 9XD

Telephone: 44 (0)131 651 1961
Fax: 44 (0)131 650 6530
Email: Paul.Skehel@ed.ac.uk

Click here for a printable 1-page CV

Biographical Profile

BSc. Biochemistry. University College London.
PhD. Developmental Biology, ICRF and Imperial College London.
Research Fellow, HHMI Centre for Neurobiology and Behaviour, Columbia University, New York.
Research Associate, Neurophysiology Division, National Institute for Medical Research, London.
Lecturer (2000-), Neuroscience, University of Edinburgh,

Research Overview

Role of VAP proteins in maintaining and regulating the function of the endoplasmic reticulum, and their misfunction in degenerative motor neuron diseases
 
The first member of the VAP family of proteins, ApVAPA (or VAP-33), was identified in Aplysia californica, by its association with the synaptic vesicle protein VAMP/Synaptobrevin, hence the nomenclature VAMP/Synaptobrevin Associated Protein.  VAP proteins are found in all eukaryotic organisms studied to date. 
Our work in Aplysia suggested that VAP proteins may be required for efficient synaptic transmission and several observations made by other groups indicate a functional role for VAP proteins in the secretory system. Other studies have suggested a more general role in membrane protein trafficking.  The MSP domain of VAP proteins can act as a FFAT domain binding motif to tether cytosolic proteins to intracellular membranes. The Hepatitis C replication complex is also localized to the ER via interactions between VAPA and the viral proteins NS5A and B.
We and our collaborators in Brazil have identification a mis-sense point mutation within the MSP domain of human vapB, VAPBP56S, that is associated with a dominant inherited form of motor neuron disease, ALS8.  The mutation causes the protein to form what appear to be aggregates throughout the cells.  We have recently shown that VAPA and VAPB can interact with an ER stress response transcription factor called ATF6, and that this association appears to reduce the activity of ATF6.  The disease-associated VAPB mutation has a more profound inhibitory affect on ATF6 than the wild type protein.  Our current work focuses on determining the molecular constituents of the VAPBP56S aggregates, and characterising the mechanistic details of the VAPB-ATF6 interaction.

School of Biomedical Sciences Research Briefing
Regulated secretion from vascular endothelial cells

Regulated secretion from vascular endothelial cells

Vascular endothelial cells (EC) regulate blood clotting and local inflammatory responses by secreting locally acting mediators including von Willebrand factor (vWF) and P-selectin. vWF and P-selectin secretion has been implicated in the early development of atherosclerosis, that typically affects only specific sites of the vasculature. Both vWF and P-selectin are stored in endothelial-specific secretory organelles called Weibel-Palade bodies (WPb). We collaborate with Dr. Tom Carter and Dr. Matthew Hannah at the NIMR, Mill Hill, to use fluorescently labelled proteins to study regulated secretion from EC cells in situ.

Collaborators

Dr. Tom Carter: National Institute for Medical Research, London
Dr. Matthew Hanna: National Institute for Medical Research, London
Dr. Rosenblum: Haifa University, Israel.
Prof. Mayana Zatz: Sao Paulo Brazil

Current Grants

Scottish Motor Neurone Disease Project Grant

Select Recent Publications

Gkogkas C, Middleton S, Kremer AM, Wardrope C, Hannah M, Gillingwater TH, Skehel P. VAPB interacts with and modulates the activity of ATF6. Hum Mol Genet. 2008 Feb 12

Babich V, Meli A, Knipe L, Dempster JE, Skehel P, Hannah MJ, Carter T. Selective release of molecules from Weibel Palade bodies during a lingering kiss. Blood. 2008 Feb 5; [Epub ahead of print]

Erent M, Meli A, Moisoi N, Babich V, Hannah MJ, Skehel P, Knipe L, Zupancic G, Ogden D, Carter T. Rate, extent and concentration dependence of histamine-evoked Weibel-Palade body exocytosis determined from individual fusion events in human endothelial cells. J Physiol. 2007 Aug 15;583(Pt 1):195-212.

Gillingwater TH, Wishart TM, Chen PE, Haley JE, Robertson K, MacDonald SH, Middleton S, Wawrowski K, Shipston MJ, Melmed S, Wyllie DJ, Skehel PA, Coleman MP, Ribchester RR. The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells.
Hum Mol Genet. 2006 Feb 15;15(4):625-35

Hannah MJ, Skehel P, Erent M, Knipe L, Ogden D, and Carter T (2005) Differential kinetics of cell surface loss of von Willebrand factor and its propolypeptide after secretion from Weibel-Palade bodies in living human endothelial cells. J Biol Chem 280: 22827-22830

Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, and Zatz M (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75: 822-831