Molecular pathogenesis of alpha-1-antitrypsin deficiency

Rev Mal Respir. 2014 Dec;31(10):992-1002. doi: 10.1016/j.rmr.2014.03.015. Epub 2014 Nov 20.

Abstract

Alpha-1 antitrypsin (α1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of α1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating α1-AT predisposes the Z α1-AT homozygote to early onset emphysema. We review here the molecular basis of α1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of α1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for α1-AT deficiency. This review considers our understanding of the pathobiology of α1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease.

Keywords: Alpha-1 antitrypsin deficiency; Conformational disease; Défaut de repliement; Déficit en alpha-1 antitrypsine; Liver disease; Maladie hépatique; Maladies conformationnelles; Misfolding; Protein evolution; Évolution protéique.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Models, Molecular
  • Protein Structure, Tertiary
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / pathology
  • Pulmonary Disease, Chronic Obstructive / therapy
  • alpha 1-Antitrypsin / chemistry
  • alpha 1-Antitrypsin Deficiency / genetics*
  • alpha 1-Antitrypsin Deficiency / pathology
  • alpha 1-Antitrypsin Deficiency / therapy

Substances

  • alpha 1-Antitrypsin