Centre staff
Dr Gail Haddock
Senior lecturer/researcher in biomedical science
Pathogenesis of multiple sclerosis and stroke
Phone 0114 225 5550
Email g.haddock@shu.ac.uk
Research interests
The role of ADAMTSs in the pathogenesis of neurological diseases
The ADAMTSs (A Disintegrin and Metalloproteinase with Thrombospondin motifs),are a group of 19 Zn-dependent metalloproteinases, -a phylogenetic subset of these enzymes that includes ADAMTS-1, -4, -5, -8, -9, -15 and -20, encompasses proteases that cleave proteoglycans and have anti-angiogenic activity. The best characterised of these are ADAMTS-1, -4 and -5 which are secreted and interact with cell surfaces and extracellular matrix (ECM) via their C-terminal ancillary domains. The only tight-binding tissue inhibitor of the ADAMTSs is tissue inhibitor of metalloproteinases (TIMP)-3 which like the ADAMTS', is sequestered in the ECM via interactions with sulfated GAGs.
Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease of the central nervous system (CNS) affecting mainly white matter. Key events in the pathogenesis of MS include breakdown of the blood-brain barrier, resulting infiltration of inflammatory cells leading (directly or indirectly) to changes in the composition of the ECM. The extracellular matrix proteins are important to brain structure through maintenance of the correct hydrodynamics and in their interactions with other ECM components.The sequence of events leading to changes in the ECM of white matter in MS are not known, nor are the enzymes that are responsible for these processes which ultimately lead to axonal loss. Alterations in turnover of the ECM contribute to disease processes and are modulated by injury. ADAMTS-1, -4 and -5 have been shown to cleave aggregating chondroitin sulphate proteoglycans (CSPGs) such as aggrecan, versican and brevican which are key components of CNS ECM. We wish to investigate the roles played in this process by the ADAMTS group.
Our research data has shown ADAMTS expression in the normal central nervous system and alteration of expression in Multiple Sclerosis (MS) and Stroke. We have also shown that ADAMTS-4 is co localised with CSPGs in brain tissue. The ability of the ADAMTSs to degrade CSPGs of the ECM and their sites of expression suggests that ADAMTS-1, -4, -5 and -9 may be important in MS pathogenesis and other neurological diseases.
Collaborators
- Dr Stuart Allen, University of Manchester
- Dr David Buttle, Sheffield University
Publications
Reid MJ, Cross AK, Haddock G, Allan SM, Stock CJ, Woodroofe MN, Buttle DJ, Bunning RAD (2009). ADAMTS-9 expression is up-regulated following transient middle cerebral artery occlusion (tMCAo) in the RAT. Neuroscience Letter 452: 252-257.
Haddock G, Cross AK, Allan S, Sharrack B, Callaghan J, Buttle DJ, Woodroofe MN (2007) Brevican and phosphacan expression and localization following transient middle cerebral artery occlusion in the rat. Biochemical Society Transactions. 35(Pt 4):692-4.
Cross AK, Allan S, Haddock G., Surr J, Bunning RAD, Buttle DJ, Stock CJ, Woodroofe MN (2006) ADAMTS-1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes. Brain Research. 1088:19-30.
Cross AK, Haddock G, Surr J, Plumb J, Bunning RAD, Buttle DJ, Woodroofe MN (2006) Differential expression of ADAMTS-1, -4, -5 and TIMP-3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis. Journal of Autoimmunity. 26:16-23.
Haddock G, Cross AK, Plumb J, Surr J, Buttle DJ, Bunning RAD and Woodroofe MN (2006) Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter. Multiple Sclerosis. 12:386-396.
Plumb J, McQuaid S, Cross AK, Surr J, Haddock G, Bunning RAD, Woodroofe MN (2006) Upregulation of ADAM-17 expression in active lesions in multiple sclerosis. Multiple Sclerosis, 12:375-386.
Plumb, J, Cross, AK, Surr, J, Haddock, G, Smith, T, Bunning, RAD, Woodroofe, MN (2005) ADAM-17 protein and mRNA expression in the spinal cord of rats with acute experimental autoimmune encephalomyelitis. J Neuroimmunology, 164:1-9
