Centre for Amyloidosis and Acute Phase Proteins
Amyloid and amyloidosis
Amyloidosis is a disorder of protein folding in which normally soluble proteins accumulate in the tissues as abnormal insoluble fibrils. These deposits damage the structure and function of the tissues and cause serious disease which is usually fatal if it affects major organs.
Amyloid deposition in the brain is always present in Alzheimer’s disease but it not known whether the amyloid itself causes dementia. Similarly, amyloid deposits are universally present in the pancreas in maturity onset diabetes and may be related to islet failure. Our team has worked on many aspects of these diseases for 30 years, and continues to elucidate fundamental molecular and pathogenetic mechanisms, develop new diagnostic procedures and introduce new and improved approaches to treatment, leading to greatly prolonged patient survival.
Our clinical service in systemic amyloidosis has been recognised and comprehensively funded directly by the UK Department of Health as the UK National Health Service National Amyloidosis Centre with Professor Philip Hawkins as Clinical Director. The Centre provides diagnostic and management advisory services to the whole national caseload and to many patients from Europe and elsewhere around the world.
Pentraxins and the acute phase response
The acute phase response is a complex adaptive response to most forms of tissue injury, infection and inflammation, that is conserved amongst all endothermic species and is characterised by increased production and circulating concentrations of a range of different plasma proteins. The first such acute phase protein to be identified was C-reactive protein (CRP) and we have worked for nearly 40 years on this and related proteins belonging to what is known as the pentraxin family. The other human pentraxin is serum amyloid P component (SAP), which is a universal constituent of amyloid deposits and contributes to their pathogenesis. We have developed a new drug (CPHPC) that specifically targets SAP and depletes it from the blood and tissues. Our initial studies suggest that the drug may be of benefit in some patients with systemic amyloidosis and we are working actively on promising new approaches using CPHPC in combination with anti-SAP antibodies. This treatment, which dramatically clears established visceral amyloid deposits in experimental models, has been licensed to GlaxoSmithKline and a full scale collaborative development programme is in progress aiming at first studies in patients with systemic amyloidosis in 2012.
Recent highlights of our work on C-reactive protein (CRP) have been in two areas. (1) Critical evaluation of the relationship between CRP values and assessment of cardiovascular disease risk shows that it has been exaggerated on the basis of early and insufficiently powered studies. Recent more extensive studies demonstrate that CRP values are neither strong nor independent predictors of cardiovascular disease risk in general populations and do not add significantly to risk assessments based on the known causal risk factors for atherothrombotic events. We have recently reviewed this field: Lowe, G.D.O. and Pepys, M.B. (2006) C-reactive protein and cardiovascular disease: weighing the evidence. Curr. Atheroscler. Rep., 8: 421-428 and Casas, J.P., Shah, T., Hingorani, A.D., Danesh, J. and Pepys, M.B. (2008) C-reactive protein and coronary heart disease: a critical review. J. Int. Med., 264: 295-314. (2) We demonstrated that authentic pure human CRP does not have the pro-inflammatory, pro-atherogenic or pro-thrombotic effects in healthy intact individuals which have been claimed by others. In marked contrast we have shown that in the presence of pre-existing tissue damage, human CRP can promote substantially greater injury via a complement dependent mechanism. We first reported this effect in models of acute myocardial infarction and stroke but it is likely to occur in many different diseases. We have therefore designed and are developing novel small molecule drugs which completely abrogate these adverse effects of CRP. Our initial results were published in Nature in 2006 and the structure of CRP complexed with our novel inhibitor compound was published on the cover, as shown here.
Structure and function
A key element of our studies of pentraxins and amyloid proteins has been the innovative crystallographic analyses conducted in collaboration with Professor Steve Wood and his colleagues who have established a Laboratory for Protein Crystallography within the UCL Centre for Amyloidosis and Acute Phase Proteins at the Royal Free Campus. Proteins purified from tissues and recombinant organisms are crystallised ready for X-ray diffraction data collection using in house instrumentation or synchrotron radiation sources
such as the European Synchrotron Radiation Facility (ESRF) in Grenoble, the DIAMOND light source in the UK. Neutron diffraction data is collected at the Institute Laue-Langevin in Grenoble or at Los Alamos.
Electron density maps are generated from the diffraction data and molecular models fitted to the density by computer graphics methods.
|A typical X-ray diffraction image recorded at ESRFand electron density images at medium and high resolution|
Recent applications of this approach have generated images of pentraxin targeted drugs bound by the proteins:
CRP with bound bis(phosphocholine)-hexane
SAP with bound CPHPC
A host of other informative structures are studied including enzymes of haem biosynthesis:
Dimer of human porphobilinogen deaminase
Octamer of yeast aminolaevulinate dehydratase
Invertebrate neuronal signal transducers and bacterial injectisome components:
|Calexcitin from Loligo pealei||BipD protein Burkholderia pseudomallei|
Enzymes involved with inositol metabolism and the degradation of aromatic xenobiotics:
|Bovine inositol monophosphatase||MhpC hydrolase from E.coli|
The degradation of superoxide anions and the cleavage of polpeptide chains at low pH:
|Superoxide dismutase from Mycobacterium tuberculosis||Endothia parasitica pepsin|
Electron transport and methanol oxidation in methylotrophic bacteria:
|Cytochrome CL from Methylobacterium extorquens and the associated methanol dehydrogenase|
|Mycobacterium tuberculosis Chaperonin 10 tetradecamer|
After initial grants from the Medical Research Council starting in 1969, our work on amyloidosis and pentraxins was funded from 1979-2009 by a Medical Research Council Programme Grant. We have also received substantial support from The Wolfson Foundation (totalling £3.5 million), The Wellcome Trust (including a £3.8 million Seeding Drug Discovery Initiative award) and other medical charities. Current grants include £4.6 million from the MRC running until 2013. Generous charitable donations by patients and their relatives and friends to the UCL Amyloidosis Research Fund, within the umbrella of the UCL Development Fund, provide flexible non-earmarked resources which are immensely helpful to our fast moving research programmes. The structural biology team, now forming the Laboratory for Protein Crystallography, has had sustained project grant support from Research Councils (EPSRC, BBSRC, MRC) and charities (Wellcome Trust, British Heart Foundation).
Page last modified on 28 oct 13 14:24 by E A ( Beth ) Jones