Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

Abstract

Human cells express large amounts of different proteins continuously that must fold into well-defined structures that need to remain correctly folded and assemble in order to ensure their cellular and biological functions. The integrity of this protein balance/homeostasis, also named proteostasis, is maintained by the proteostasis network (PN). This integrated biological system, which comprises about 2000 proteins (chaperones, folding enzymes, degradation components), control and coordinate protein synthesis folding and localization, conformational maintenance, and degradation. This network is particularly challenged by mutations such as those found in genetic diseases, because of the inability of an altered peptide sequence to properly engage PN components that trigger misfolding and loss of function. Thus, deletions found in the ∆F508 variant of the Cystic Fibrosis (CF) transmembrane regulator (CFTR) triggering CF or missense mutations found in the Z variant of Alpha 1-Antitrypsin deficiency (AATD), leading to lung and liver diseases, can accelerate misfolding and/or generate aggregates. Conversely to CF variants, for which three correctors are already approved (ivacaftor, lumacaftor/ivacaftor, and most recently tezacaftor/ivacaftor), there are limited therapeutic options for AATD. Therefore, a more detailed understanding of the PN components governing AAT variant biogenesis and their manipulation by pharmacological intervention could delay, or even better, avoid the onset of AATD-related pathologies.

Pathological Aspects of COVID-19 as a Conformational Disease and the Use of Pharmacological Chaperones as a Potential Therapeutic Strategy

“…In addition, AAT inhibits the activity of neutrophil serine proteases in blood. Thus, the deficiency of properly folded AAT causes the activation of neutrophil serine proteases, resulting in lung injury (Karatas and Bouchecareilh, 2020). Cystic fibrosis, another example of a genetic disorder, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is a chloride ion channel expressed on the epithelial cells of the lung, pancreas, and other organs.…”

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“…123,124 Although only a small proportion of individuals with COPD have alpha-1-antitrypsin deficiency, recognition of the genetic mutations that cause reduced functional alpha-1-antitrypsin within the lung and increased risk of emphysema leads to specific therapy with alpha-1-antitrypsin replacement. 125,126 The current mainstays of COPD maintenance therapy consist of three classes of inhaled medications: β-agonists, muscarinic antagonists, and corticosteroids. Bronchodilators started as short-acting medications such as albuterol and ipratropium with durations of effect lasting from 2 to 6 h. Next, long-acting medications with effects lasting up to 12 h were discovered and, most recently, ultralong acting drugs that only require daily dosing have been developed and clinically tested.…”

“… 123 , 124 Although only a small proportion of individuals with COPD have alpha-1-antitrypsin deficiency, recognition of the genetic mutations that cause reduced functional alpha-1-antitrypsin within the lung and increased risk of emphysema leads to specific therapy with alpha-1-antitrypsin replacement. 125 , 126 …”

The Autophagy Pathway: A Critical Route in the Disposal of Alpha 1-Antitrypsin Aggregates That Holds Many Mysteries

“…The Z mutant is caused by a single mutation at protein residue 342 leading to a lysine to glutamate substitution. This point mutation results in a misfolded protein that is retained within the ER of hepatocytes as two different forms: the soluble/monomer form [ 8 , 9 ], and also the insoluble/aggregate form [ 10 ]. Indeed, this single point mutation predisposes Z-AAT protein to polymerization and aggregation in the ER.…”