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    The serpinopathies: studying serpin polymerization in vivo

    Irving, J.A. and Ekeowa, U.I. and Belorgey, D. and Haq, I. and Gooptu, Bibek and Miranda, E. and Pérez, J. and Roussel, B.D. and Ordóñez, A. and Dalton, L.E. and Thomas, S.E. and Marciniak, S.J. and Parfrey, H. and Chilvers, E.R. and Teckman, J.H. and Alam, S. and Mahadeva, R. and Rashid, S.T. and Vallier, L. and Lomas, D.A. (2011) The serpinopathies: studying serpin polymerization in vivo. In: Whisstock, J.C. and Bird, P. I. (eds.) Serpin Structure and Evolution. Methods In Enzymology 501. New York, U.S.: Elsevier, pp. 421-466. ISBN 9780123859501.

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    Abstract

    The serpinopathies result from point mutations in members of the serine protease inhibitor or serpin superfamily. They are characterized by the formation of ordered polymers that are retained within the cell of synthesis. This causes disease by a “toxic gain of function” from the accumulated protein and a “loss of function” as a result of the deficiency of inhibitors that control important proteolytic cascades. The serpinopathies are exemplified by the Z (Glu342Lys) mutant of α1-antitrypsin that results in the retention of ordered polymers within the endoplasmic reticulum of hepatocytes. These polymers form the intracellular inclusions that are associated with neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. A second example results from mutations in the neurone-specific serpin–neuroserpin to form ordered polymers that are retained as inclusions within subcortical neurones as Collins’ bodies. These inclusions underlie the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. There are different pathways to polymer formation in vitro but not all form polymers that are relevant in vivo. It is therefore essential that protein-based structural studies are interpreted in the context of human samples and cell and animal models of disease. We describe here the biochemical techniques, monoclonal antibodies, cell biology, animal models, and stem cell technology that are useful to characterize the serpin polymers that form in vivo.

    Metadata

    Item Type: Book Section
    Keyword(s) / Subject(s): Serpin polymerization, Antitrypsin, Neuroserpin, FENIB, Cirrhosis, Biochemistry, Monoclonal antibodies, Cell biology, Animal models, Stem cell technology
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 24 Jun 2015 14:29
    Last Modified: 06 Dec 2016 10:42
    URI: http://eprints.bbk.ac.uk/id/eprint/12443

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