Professor David A Lomas
Home | Research Profile | Key Publications
The serpinopathies and Alzheimer’s disease: disease mechanisms and therapeutic interventions
One in twenty-five of the Northern European population carry the Z allele (342Glu®Lys) of a1-antitrypsin. Homozygotes for this mutation retain a1-antitrypsin within hepatocytes as inclusion bodies that are associated with neonatal hepatitis, juvenile cirrhosis and hepatocellular carcinoma. We have shown that Z a1-antitrypsin is retained within the endoplasmic reticulum of hepatocytes by a unique protein-protein interaction between the reactive centre loop of one molecule and b-sheet A of a second. The structure and significance of these loop-sheet polymers has been confirmed using biochemical, biophysical, crystallographic, and cell biology studies and with monoclonal antibodies and animal models of disease. Stefan Marciniak’s team is determining the cellular consequences of the accumulation of proteins in the endoplasmic reticulum. We are now using data from our in silico screens as lead molecules to identify compounds with a better structure/activity relationship that can prevent the polymerisation of mutant a1-antitrypsin in vitro and in vivo. This work is being developed in collaboration with the pharmaceutical industry. Alpha-1-antitrypsin is a member of the serine protease inhibitors or serpin superfamily of proteins. We have shown that mutants of another serpin, neuroserpin, also polymerise within neurones to cause an inclusion body dementia that we have called familial encephalopathy with neuroserpin inclusion bodies (FENIB). We have described 5 families with FENIB caused by 4 different mutations and have demonstrated a clear correlation between genotype and phenotype based on the rate of polymer formation. We are dissecting the mechanism of polymerisation of mutants of neuroserpin and determining how these cause neurotoxicity with biochemical, cell and Drosophila models of disease. Finally, we have demonstrated that neuroserpin is also important in the far more common dementia caused by Alzheimer's disease. Indeed we have shown a specific interaction between the Alzheimer's Ab peptide and neuroserpin and have demonstrated that this interaction is neuroprotective in cell and Drosophila models of disease. This interaction was assessed by the development of a Drosophila model over-expressing the Ab peptide. This fly has a marked neuronal phenotype with reductions in longevity and locomotor activity. Damian Crowther is leading the programme of work to identify modifiers of the toxicity of the Ab peptide and we are working with Chris Dobson’s group (Chemistry) to develop algorithms to link peptide aggregation with toxicity in vivo. Our long term goal is to understand the pathways of cell toxicity in serpin polymer mediated syndromes (the serpinopathies) and in Alzheimer's disease and to develop novel therapeutic strategies.
Funding
- Medical Research Council
- Wellcome Trust
- EPSRC
- Diabetes UK
- GlaxoSmithKline
- British Lung Foundation
- BBSRC
- Children’s Liver Disease Foundation
Links
Group Members
-
© 2010 CIMR, University of Cambridge
- Privacy policy
- Information provided by webmaster@cimr.cam.ac.uk.