- 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
Our general interests are the mechanisms of neurodegeneration. More specifically Motor Neuron Disease, also known as Amyotrophic Lateral Sclerosis or ALS. Our current work focuses on ALS8, a disease caused by mutations in the VAPB gene.
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.
Together with our collaborators in Brazil we identified a mis-sense point mutation, VAPBP56S, within the MSP domain of human vapB, as a causes of ALS8. The mutation causes the protein to form what appear to be aggregates throughout the cells, and influences interactions with ER stress response factors such as ATF6.
In neurons a fraction of VAPB is truncated to generate separate MSP and C-terminal domains. These truncated forms do not appear to be generated from the ALS8 mutant protein.
Our current work focuses on determining the mechanisms of VAPB function and 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.