Effects of alpha1-antitrypsin polymerisation on organelle structure and fluidity in hepatocytes

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Individuals with alpha1-antitrypsin deficiency are at increased risk of lung and liver disease. The lung disease arises because blood levels of antitrypsin are too low to protect against damage caused by lung inflammation. The liver disease results from the accumulation of an abnormal form of antitrypsin inside a part of the liver cell called the endoplasmic reticulum (or ER for short). For reasons that remain unclear, the accumulation of polymers of antitrypsin within the ER increases the chances of an individual developing liver cirrhosis (scarring) or liver cancer. No current therapy targets the liver disease of antitrypsin deficiency. We wish to understand how antitrypsin polymers affect ER function, so that we can develop new liver-protective treatments.Many diseases are caused by a type of ER malfunction called "ER stress". The purpose of the ER is to manufacture secreted proteins, like antitrypsin. New proteins are "folded" within the ER into their unique shape that allows them to perform their specific role in the body. ER stress arises when newly made ER proteins fail to fold correctly, for example due to an inherited mutation of that protein. This "misfolding" causes the new proteins to stick together randomly, damaging the cell and triggering inflammation. In contrast to these random aggregates, the most common mutated forms of alpha1-antitrypsin form ordered chains of "polymers" that we and others have shown do not cause ER stress directly. Instead, they make the cell more sensitive to other stresses, such as toxic chemicals or high temperatures, which can trigger ER stress more easily. The reason why polymers of antitrypsin cause this increased sensitivity is not known, although we previously showed that antitrypsin polymers impair the movement of normal proteins inside the ER. This might impair the folding of normal proteins.We previously developed new technologies that allow us to determine how polymers of alpha1-antitrypsin alter the biology of the ER, for example changing its viscosity. We aim to use advanced microscopy techniques to watch how antitrypsin and other proteins move inside the ER, while also observing the efficiency of protein folding using other technologies we have developed. By combining these new techniques, we will understand how polymers of antitrypsin change the environment inside the ER and how this changes the cell's sensitivity to ER stress. Using this new knowledge, we will manipulate the ER in liver cell aiming to return its behaviour to normal. We will then test if this prevents the abnormal signalling that is responsible for patients with alpha1-antitrypsin deficiency developing liver scarring (cirrhosis) and inflammation. The results of this project identify new targets for drug development they may allow us to prevent the liver disease seen in alpha1-antitrypsin deficiency.