AATD Prognosis
Genetic research abstract – Alpha 1-antitrypsin deficiency

Alpha-1 antitrypsin deficiency (AATD) is a disease in which a defect occurs in the production of the alpha-1 antitrypsin (AAT) protein. Meseeha and Attia explained its significance: “AAT protein protects the body from the neutrophil elastase enzyme which is released from white blood cells to fight infection. This inherited disorder leads to decreased AAT activity in the blood and lung and deposition of excessive abnormal AAT protein in the liver.” 

What drives this defective production of AAT? Padilla-Godínez et al think it has to do with protein misfolding. They wrote, “Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including . . . AATD.” 

The Importance of Proteostasis 

Let’s discuss the significance of proteins in human biology. “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,” Karatas and Bouchecareilh wrote. 

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The integrity of protein balance and homeostasis is maintained by what is known as the “proteostasis network”. “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,” Karatas and Bouchecareilh explained. 

Most proteins possess a 3-dimensional structure according to their amino acid sequence. Protein misfolding occurs when proteins take on abnormal spatial configurations. These misfolded proteins can aggregate and lead to diseases such as AATD. 

The endoplasmic reticulum (ER) is a cellular compartment that plays a key role in proteostasis, functioning as a sort of checkpoint for almost all secreted proteins. The ER is involved in the synthesis, folding, and structural maturation of nearly half of all proteins. “This ER-proteostasis is maintained and ensured by a specific protease network consisting of ER-resident enzymes, such as chaperones, glycosylating enzymes, and oxido-reductases,” Karatas and Bouchecareilh wrote. 

Because of the central role that the ER plays in regulating protein, “the ER proteostasis imbalance is at the root/hallmark of a variety of human diseases,” they explained. “Hypoxia, nutrient deprivation, proteasome dysfunction, or mutations in its client proteins can cause loss in ER proteostasis and lead to accumulation of misfolded proteins and aggregates into the ER, a condition encountered in AATD.” 

The Connection With AATD

We have established that protein misfolding can lead to a number of diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and more. We will now focus our attention on how protein misfolding leads to AATD.

The main function of AAT is to protect lung tissue by inhibiting serine proteases neutrophil elastase, cathepsin G, and proteinase 3. It is encoded by the serpin family A member 1 (SERPINA) gene. “Like all serine protease inhibitors, AAT’s characteristic secondary structure can suffer alterations due to mutations in the SERPINA1 gene, which can lead to non-functional proteins that can polymerize and accumulate: these conditions are known as serpinopathies,” Padilla-Godínez et al wrote. 

In normal individuals, AAT is synthesized in the free ribosomes, translocated into the rough ER, and undergoes posttranslational modifications to be activated and released into the bloodstream. 

In AATD, mutations in the SERPINA1 gene can result in protein misfolding. The misfolded proteins then aggregate into polymeric chains of AAT, which occurs in the ER of hepatocytes. This then impairs hepatocyte function, resulting in liver injury. Depending on the type of mutation, AATD can be classified as either mild or severe. Among the common complications of AATD are chronic obstructive pulmonary disease (COPD), panniculitis, and cirrhosis. 

We know that altered AAT can polymerize and accumulate in the ER; however, “the precise mechanism of polymerization in the ER remains largely unknown, mostly due to the heterogeneity of ex vivo polymers that makes them unsuitable for crystallography,” Padilla-Godínez and colleagues wrote. 

The Limitations of Autophagy 

The body has a method to degrade misfolded AAT: autophagy. “To prevent the accumulation of potentially harmful structures such as the Z-aggregates, cells use another highly conserved degradation pathway, named autophagy, to target large structures/aggregate forms to the degradation by the lysosome,” Karatas and Bouchecareilh explained. 

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However, the clearance provided by autophagy is not thorough enough to prevent misfolded AAT aggregates from remaining within inclusions, causing liver damage and fibrosis. Some scientists therefore think that the induction of autophagy may limit the damage that these proteins can cause.

“In view of the above, several studies have shown that induction of autophagy reduced the presence of such conditions, so attention has been focused on the signaling pathways and proteins involved in the autophagy process in the presence of Z-AAT [AAT produced as a result of the Z-AAT mutation] aggregation in the search to improve the response,” Padilla-Godínez and colleagues wrote.

The hope here is that by understanding the pathological processes that contribute to AAT etiology, scientists will be better positioned to develop therapies that directly address them. “Researchers might be capable of developing better procedures to diminish or prevent the misfolding and aggregation process of these proteins, as well as improving the defensive proteolytic pathways,” Padilla-Godínez et al wrote. 


Meseeha M, Attia M. Alpha 1 antitrypsin deficiency. In: StatPearls. StatPearls Publishing; 2021. Accessed December 20, 2021.

Karatas E, Bouchecareilh M. Alpha 1-antitrypsin deficiency: a disorder of proteostasis-mediated protein folding and trafficking pathwaysInt J Mol Sci. Published online February 21, 2020. doi:10.3390/ijms21041493

Padilla-Godínez FJ, Ramos-Acevedo R, Martínez-Becerril HA, et al. Protein misfolding and aggregation: the relatedness between Parkinson’s disease and hepatic endoplasmic reticulum storage disordersI J Mol Sci. 2021; 22(22):12467. doi:10.3390/ijms222212467