Modelling human proteostasis and organelle homeostasis disorders in yeast and its application in drug discovery

Disruptions in cellular homeostasis and proteostasis are central to many human diseases, yet direct mechanistic investigation in human systems remains constrained by biological complexity and ethical limitations. Therefore, researchers have turned to the use of model systems that allow the more efficient dissection of fundamental cellular processes. The unicellular yeast Saccharomyces cerevisiae has emerged as a powerful eukaryotic model for studying disorders driven by defects in homeostasis and proteostasis. The relevant processes are highly conserved in yeast, enabling precise genetic manipulation and real-time analysis of mechanisms that are difficult to study in mammalian systems. Yeast models have been deployed to study prion propagation, lysosomal enzyme trafficking, and mitochondrial dysfunction. Yeast also provides a versatile platform for drug discovery, particularly through the use of the yeast two-hybrid system and high-throughput screens. Despite an inability to recapitulate the full complexity of multicellular organisms, yeast remains an invaluable tool for investigating human diseases and for the development of therapeutics. This review highlights how yeast has uniquely advanced the understanding of human diseases including those associated with prions, lysosomal proteins, and mitochondria and can be combined with the utility of yeast in drug discovery-collectively establishing yeast as a model for studying human disorders.