Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates.

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.