title: The serpinopathies studying serpin polymerization in vivo.
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.
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Irving
authors.forename: Ugo I
authors.initials: UI
authors.lastname: Ekeowa
authors.forename: Didier
authors.initials: D
authors.lastname: Belorgey
authors.forename: Imran
authors.initials: I
authors.lastname: Haq
authors.forename: Bibek
authors.initials: B
authors.lastname: Gooptu
authors.forename: Elena
authors.initials: E
authors.lastname: Miranda
authors.forename: Juan
authors.initials: J
authors.lastname: Pérez
authors.forename: Benoit D
authors.initials: BD
authors.lastname: Roussel
authors.forename: Adriana
authors.initials: A
authors.lastname: Ordóñez
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Dalton
authors.forename: Sally E
authors.initials: SE
authors.lastname: Thomas
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
authors.forename: Helen
authors.initials: H
authors.lastname: Parfrey
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Teckman
authors.forename: Sam
authors.initials: S
authors.lastname: Alam
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahadeva
authors.forename: S Tamir
authors.initials: ST
authors.lastname: Rashid
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D000818:Animals; D001703:Biophysics / Q000379:methods*; D018929:Cell Culture Techniques; D002460:Cell Line; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments; D017354:Point Mutation; D058105:Polymerization; D011485:Protein Binding; D011487:Protein Conformation; D059748:Proteolysis; D015843:Serpins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000097522:Neuroserpin
chemical_list: D009479:Neuropeptides; D010446:Peptide Fragments; D015843:Serpins; D000515:alpha 1-Antitrypsin; D000097522:Neuroserpin