Misfolded but not Malicious: Prion Proteins in Budding Yeast

Prion proteins, although frequently associated with neurodegenerative diseases, are not universally harmful to cells. Instead, prions may serve as a beneficial epigenetic mechanism, allowing cells to alter their phenotype to adapt to adverse environmental conditions. Prions form when a protein adopts alternate and stable folding conformation. The Garcia Lab aims to identify beneficial prions using the budding yeast, Saccharomyces cerevisiae. We are particularly interested in prion conformations of RNA modifying enzymes (RMEs), because these proteins can affect the expression of many genes simultaneously. After screening hundreds of yeast strains, the Garcia Lab identified six strains of yeast – associated with potentially alternate conformations of the RMEs Abd1, Cet1, Ppm2, Pus4, Pus6 and Trm5 – that exhibited resistance to harmful chemicals. Extensive tests are needed to confirm that their resistance to stress is caused by a prion-based conformation of the RNA modifying enzymes. Here, experiments describing the meiotic inheritance, protein dependance, and cytoplasmic inheritance of these resistance phenotypes are presented. The initial results are key to attributing the previously identified growth states to a prion conformation of each of the six RNA modifying enzymes. The Garcia lab will continue to investigate these putative prions in future experiments to determine the mechanism for resistance. This research represents an important contribution to our understanding of prions as a protein-based epigenetic mechanism and their effects on key cell processes

Hunting for Prions: Propagating Putative Prion States in Budding Yeast

Prions have been closely associated with fatal neurodegenerative diseases. Recent evidence, however, suggests that prions also represent an additional class of epigenetic mechanism that is biologically beneficial. From an evolutionary standpoint, the ability to change phenotypes without requiring changes to the genome, as prions do, would be hugely beneficial in fluctuating environments. Through overexpressing proteins and introducing environmental stressors, two techniques known to increase de novo prion formation, we performed a large-scale screen of many RNA-modifying enzymes in budding yeast to test if they harbor beneficial prionogenic behavior. From this screen, six induced prion-like states were found to be mitotically stable and infectious. We show that many of these putative prions are dominant and are dependent on chaperone proteins, which is consistent with a prion-based epigenetic mechanism. Prion-based inheritance is expanding on the central dogma of biology, contributing to the belief that prions work as an epigenetic mechanism for passing on heritable traits