Abstract
The classical form of α1-antitrypsin deficiency (ATD) is an autosomal co-dominant disorder that affects ~1 in 3000 live births and is an important genetic cause of lung and liver disease. The protein affected, α1-antitrypsin (AT), is predominantly derived from the liver and has the function of inhibiting neutrophil elastase and several other destructive neutrophil proteinases. The genetic defect is a point mutation that leads to misfolding of the mutant protein, which is referred to as α1-antitrypsin Z (ATZ). Because of its misfolding, ATZ is unable to efficiently traverse the secretory pathway. Accumulation of ATZ in the endoplasmic reticulum of liver cells has a gain-of-function proteotoxic effect on the liver, resulting in fibrosis, cirrhosis and/or hepatocellular carcinoma in some individuals. Moreover, because of reduced secretion, there is a lack of anti-proteinase activity in the lung, which allows neutrophil proteases to destroy the connective tissue matrix and cause chronic obstructive pulmonary disease (COPD) by loss of function. Wide variation in the incidence and severity of liver and lung disease among individuals with ATD has made this disease one of the most challenging of the rare genetic disorders to diagnose and treat. Other than cigarette smoking, which worsens COPD in ATD, genetic and environmental modifiers that determine this phenotypic variability are unknown. A limited number of therapeutic strategies are currently available, and liver transplantation is the only treatment for severe liver disease. Although replacement therapy with purified AT corrects the loss of anti-proteinase function, COPD progresses in a substantial number of individuals with ATD and some undergo lung transplantation. Nevertheless, advances in understanding the variability in clinical phenotype and in developing novel therapeutic concepts is beginning to address the major clinical challenges of this mysterious disorder.
Highlights
Introduction α1-antitrypsin deficiency (ATD) was first described 50 years ago when absence of the α1-globulin fraction was noticed in the serum specimens of individuals with chronic obstructive pulmonary disease (COPD; Box 1 provides a glossary of clinical terms) (Laurell and Eriksson, 1963)
In yeast rendered autophagy-deficient by a mutation in ATG6, antitrypsin Z (ATZ) disposal is only impaired when levels of expression are high (Kruse et al, 2006). These results suggest that the ERassociated degradation (ERAD)/proteasomal pathway can handle ATZ at lower levels of expression, presumably because it is capable of degrading soluble forms of ATZ, but at higher levels of expression, as ATZ accumulates in polymers and insoluble aggregates, autophagy becomes critical for ATZ degradation
Conclusions and future directions ATD is unique in that the disease phenotype in one target organ, the lung, is caused by a loss-of-function mechanism, whereas, in another organ, the liver, it is caused by gain-of-function proteotoxicity
Summary
Adaptations or what have been called ‘proteostasis’ mechanisms. Cell line and mouse models with inducible expression of ATZ have been valuable for identification of these pathways because these types of systems are less prone to cellular adaptations that potentially occur in systems with constitutive expression of the mutant protein. In our initial study of CBZ, we speculated that a mechanism independent of TOR (target of rapamycin) kinase was involved in the autophagy-enhancing activity because we could not detect any effect of rapamycin on cellular ATZ load in a mammalian cell line or in the liver of the ATD mouse model (Hidvegi et al, 2010). Consistent with this, it seems that one of the phenothiazines discovered to enhance autophagic degradation of Huntington mediates its effects by a TORindependent mechanism (Xia et al, 2010).
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