Dr Paul Skehel
My research focuses on the role of VAP proteins in maintaining and regulating the function of the endoplasmic reticulum, and their misfunction in degenerative motor neuron diseases.
Personal profile
- 2001-present: The University of Edinburgh
- 1996-2000: Research Associate with Dr. Tim Bliss, Division of Neurophysiology, National Institute for Medical Research, Mill Hill, London
- 1992-1996: Research Associate with Prof Eric Kandel, Howard Hughes Medical Institute, Centre for Neurobiology and Behaviour, College of Physicians and Surgeons of Collumbia University, New York, New York
- 1991: PhD Imperial Cancer Research Fund, Clare Hall
- 1987: BSc Biochemistry, University College London
Research
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 identified 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, Amyotrophic Lateral Sclerosis type VIII (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 how VAP proteins regulate the transcriptional component of ER stress responses.
In so doing we hope to provide information on the molecular details of the motor neuron disease process.
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 National Institute for Medical Research, Mill Hill, who use fluorescently labeled proteins to study regulated secretion from EC cells in situ.
Figure 1
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Funding
- Scotish Motor Neuron Disease Association (previously by The Wellcome Trust and The Royal Society)
Team members
- Ghristos Gkogkas (PhD student)
- Caroline Wardrope (Postdoc)
Collaborations
- 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
Publications
Gkogkas C, Middleton S, Kremer AM, Wardrope C, Hannah M, Gillingwater TH and Skehel P (2008) VAPB interacts with and modulates the activity of ATF6. Human Molecular Genetics 17(11):1517-26.
Babich V, Meli A, Knipe L, Dempster JE, Skehel P, Hannah MJ and Carter T (2008) Selective release of molecules from Weibel Palade bodies during a lingering kiss. Blood 111(11):5282-90.
Erent M, Meli A, Moisoi N, Babich V, Hannah MJ, Skehel P, Knipe L, Zupancic G, Ogden D and Carter T (2007) Rate, extent and concentration dependence of histamine-evoked Weibel-Palade body exocytosis determined from individual fusion events in human endothelial cells. Journal of Physiology 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 and Ribchester RR (2006) The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells. Human Molecular Genetics Feb 15;15(4):625-35.
This article was published on Apr 16, 2010