title: Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates.
abstract: Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic and/or environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease.
authors: Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15217, USA. David.perlmutter@chp.edu
authors: David H
authors: DH
authors: Perlmutter
mesh_terms: D000818:Animals; D001343:Autophagy; D002220:Carbamazepine / Q000378:metabolism / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000378:metabolism*
chemical_list: D000515:alpha 1-Antitrypsin; D002220:Carbamazepine; D046988:Proteasome Endopeptidase Complex