α1-antitrypsin deficiency and the hepatocytes - an elegans solution to drug discovery

Abstract

Hepatocytes are metabolically active cells of the liver that play an important role in the biosynthesis of proteins including α1-antitrypsin. Mutations in the α1-antitrypsin gene can lead to protein misfolding, polymerization/aggregation and retention of protein within the endoplasmic reticulum of hepatocytes. The intracellular accumulation of α1-antitrypsin aggregates can lead to liver disease and increased likelihood of developing hepatocellular carcinomas. Of note, only ~10% of individuals with α1-antitrypsin-deficiency develop severe liver disease suggesting that there are other genetic and/or environmental factors that determine disease outcome. The nematode, Caenorhabditis elegans, is a powerful genetic model organism to study molecular aspects of human disease. In this review, we discuss the functional similarities between the intestinal cells of C. elegans and human hepatocytes and how a C. elegans model of α1-antitrypsin-deficiency can be used as a tool for identifying genetic modifiers and small molecule drugs.

Keywords: C. elegans; Hepatocyte; Liver disease; Protein aggregation; α1-Antitrypsin deficiency.

Figure 1

Schematic of C. elegans intestinal cells showing the different fate of wild-type ATM and mutant ATZ proteins. Wild-type ATM travels through the ER-golgi secretory pathway and is efficiently secreted out of the cell (A). In contrast mutant ATZ protein forms polymers/aggregates within the ER and fails to be secreted (B).

Figure 2. High-content assay for the analysis of transgenic animals expressing the wild-type (ATM) and mutant (ATZ) forms of human α1-antitrypsin (AT) fused to GFP

(Gosai, Kwak, 2010) Brightfield (A and D) and fluorescent (B–C and E–F) images of animals expressing sGFP::ATM (upper panel) and sGFP::ATZ (lower panel). Note the accumulation of GFP-positive, protein aggregates in (F) that is lacking in (C). Bar graphs showing the average number of transgenic animals in each well (G) and the average number (H), area (I) and intensity (J) of the protein aggregates detected within the intestinal cells of animals expressing wild-type ATM (blue) and mutant ATZ (red). Figure reproduced from (Gosai, Kwak, 2010).