Dr. Mila Ljujuc

Role of autophagy in modifying the cellular response in alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency (AATD) is a disorder that affects lungs and/or liver and is caused by aberrant folding, trafficking and secretion of alpha-1 antitrypsin (AAT). Autophagy is a major feature of cellular response to the AAT retention within the cell and plays an important role in pathogenesis of AATD. Expression of Z-AAT, the most common deficient variant, has been shown sufficient to induce autophagy. Also, autophagy-enhancing drugs have been shown to reduce the cellular load of mutant ZAAT. Role of cellular homeostasis and proteostasis in AATD is exemplified by the study on fibroblasts from symptomatic and asymptomatic individuals with ZZ genotype that showed that cells of individuals affected by liver disease react differently to Z-AAT overexpression compared to the cells from unaffected individuals. Beclin1 is a key initiator of autophagy and a tumour suppressor whose haploinsufficiency affects cell survival. A study on yeast model has shown that Atg6, yeast homolog of mammalian Beclin1, is required for disposal of accumulated Z-AAT. However, studies on the role of Beclin1 in stress response to Z-AAT expression in mammalian cells are lacking.

Aim:

Our overall aim is to identify how autophagy affects and regulates cellular response in AATD. We wish to explore whether changes in Beclin1 expression affect stress response to Z-AAT overexpression.

The specific aims of this study are:

• Objective 1: To establish cell lines (A549 & CHO-K1) with partial (to mimic haplo-insufficiency) and complete Beclin1 knock-down;
• Objective 2: To monitor markers of ER stress, apoptosis and autophagy in cells with normal and altered Beclin1 expression that overexpress Z-AAT;
• Objective 3: - To monitor markers of necroptosis in cells expressing Z-AAT with normal and altered Beclin1 expression which would be the first study on this form of cell death in AATD

A long-term objective of this proposal is to understand mechanisms of cell death and maladaptive pathways in AATD which would help identify potential therapy targets.

Curriculum Vitae Dr. Mila Ljujic

Mila received her BSc in Molecular Biology and Physiology from the University of Belgrade in 2005. After that she started working at the Institute of Molecular Genetics and Genetic Engineering, University of Belgrade where she undertook her PhD research. Her areas of research included molecular characterisation of rare AAT variants as well as molecular mechanisms in AATD. She completed her PhD thesis in 2012 and from 2012 to 2015 was a Research Associate at Institute of Molecular Genetics and Genetic Engineering, University of Belgrade. She is currently a postdoctoral researcher at the Apoptosis Research Centre (ARC), NUI Galway where she works on endoplasmic reticulum stress and unfolded protein response and their cross-talk with other cellular processes.

Her ALTA project "Role of autophagy in modifying the cellular response in alpha-1 antitrypsin deficiency" aims to identify how autophagy affects and regulates cellular response in AATD. She wishes to explore whether changes in Beclin1 expression affect stress response to Z-AAT overexpression.

Contact
Dr. Mila Ljujic
Apoptosis Research Centre (ARC)
Biosciences
NUI Galway
Newcastle Road
Dangan
Galway, Ireland