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 alpha-1-antitrypsin. Homozygotes for this mutation retain alpha-1-antitrypsin within hepatocytes as inclusion bodies that are associated with neonatal hepatitis, juvenile cirrhosis and hepatocellular carcinoma. We have shown that Z alpha-1-antitrypsin is retained within hepatocytes by a unique protein-protein interaction between the reactive centre loop of one molecule and beta-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. We are now using in silico screening to identify compounds that can bind to, and prevent the polymerisation of, mutant alpha-1-antitrypsin in vitro and in vivo. 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 A-beta peptide and neuroserpin and have demonstrated that this interaction is neuroprotective in cell and Drosophila models of disease. 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
- Merck, Sharpe and Dohme
- Wenner-Gren Center
- Alzheimer’s Research Trust
- EPSRC
Group members
- Didier Belorgey
- Robin Carrell
 Dr Damian Crowther - Damian Crowther
- Ugo Ekeowa
- Peter Hagglof
- Susanna Karlsson-Li
- Heike Kroeger
- Beinan Liu
- Ian MacLeod
- Stefan Marciniak
- Claire Michel
- Elena Miranda
- Aileen Moloney
- Alison Warrington
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