The serpinopathies: Studying serpin polymerization in vivo

James A Irving, Ugo I Ekeowa, Didier Belorgey, Imran Haq, Bibek Gooptu, Elena Miranda, Juan Pérez, Benoit D Roussel, Adriana Ordóñez, Lucy E Dalton, Sally E Thomas, Stefan J Marciniak, Helen Parfrey, Edwin R Chilvers, Jeffrey H Teckman, Sam Alam, Ravi Mahadeva, S Tamir Rashid, Ludovic Vallier, David A Lomas

Research output: Chapter in Book/Report/Conference proceedingChapter

31 Citations (Scopus)

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.
Original languageEnglish
Title of host publicationMethods in Enzymology
EditorsJames C. Whisstock, Phillip I. Bird
PublisherAcademic Press
Pages421-466
Number of pages46
Volume501
ISBN (Print)9780123859501
DOIs
Publication statusPublished - 2011

Publication series

NameMethods in Enzymology
PublisherAcademic Press
Volume501
ISSN (Print)0076-6879
ISSN (Electronic)1557-7988

Keywords

  • Animals
  • Biophysics
  • Cell Culture Techniques
  • Cell Line
  • Epilepsies, Myoclonic
  • Heredodegenerative Disorders, Nervous System
  • Humans
  • Image Processing, Computer-Assisted
  • Induced Pluripotent Stem Cells
  • Lung
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Neuropeptides
  • Neutrophils
  • Peptide Fragments
  • Point Mutation
  • Polymerization
  • Protein Binding
  • Protein Conformation
  • Proteolysis
  • Serpins
  • Transfection
  • alpha 1-Antitrypsin

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