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.
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.
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.
Brown R, Dissanayake KN, Skehel PA, Ribchester RR. (2014) Endomicroscopy and electromyography of neuromuscular junctions in situ. Ann Clin Transl Neurol. 1(11):867-83.
Clarkson YL, Perkins EM, Cairncross CJ, Lyndon AR, Skehel PA, Jackson M. (2014) β-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: protein complex critical for sodium channel activity is impaired by SCA5-associated mutations. Hum Mol Genet. 23(14):3875-82.
Qiu J, Tan YW, Hagenston AM, Martel MA, Kneisel N, Skehel PA, Wyllie DJ, Bading H, Hardingham GE (2013). Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals. Nat Commun.4:2034.
Soriano FX, Chawla S, Skehel P, Hardingham GE (2013). SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites. J Neurochem. 124(1):26-35.
Leng G, Skehel P (2011). Polyuria, polydipsia, and poly(A) tails: insights into the adaptive nature of the cellular stress response pathways. Endocrinology. 152(12):4475-7.
Gkogkas C, Wardrope C, Hannah M, Skehel P (2011). The ALS8-associated mutant VAPB(P56S) is resistant to proteolysis in neurons. J Neurochem. Apr;117(2):286-94.
Gkogkas C, Middleton S, Kremer AM, Wardrope C, Hannah M, Gillingwater TH, Skehel P (2008). VAPB interacts with and modulates the activity of ATF6. Hum Mol Genet. Jun 1;17(11):1517-26.
Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Nov;75(5):822-31.
Mouse VAP33 is associated with the endoplasmic reticulum and microtubules. Skehel PA, Fabian-Fine R, Kandel ER. Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1101-6.
A VAMP-binding protein from Aplysia required for neurotransmitter release. Skehel PA, Martin KC, Kandel ER, Bartsch D. Science. 1995 Sep 15;269(5230):1580-3.