Investigation of de novo formation and toxicity associated with yeast prions

Prions are self-perpetuating, infectious, aggregated proteins that are associated with several neurodegenerative diseases in mammals and heritable traits in yeast. In this thesis, two aspects, common to both yeast and mammalian prion biology are explored. The first study examines the species barrier that limits the efficient transfer of prions from one species to another. The study explores whether prions from one yeast species can transfer the prion state to a prion protein from another yeast species. We find that the yeast prions [PSI+] and [PIN +] from one yeast species, S. cerevisiae, enhance the conversion of the prion domain of another yeast species, P. methanolica , to its prion form. We also find that the conversion follows many aspects of a heterologous seeding event, to give rise to newly forming prion particles.;The second study explores the toxicity related to the yeast prion [ PSI+], the prion form of Sup35p. Unlike in mammals, yeast prions are not always associated with the death of the organism. However, overexpression of Sup35p, in [PSI+] yeast causes a growth defect. We find that this growth defect is likely caused by the sequestration of either Sup35p itself or its functional binding partner, Sup45p. Thus, toxicity due to prions can occur by sequestration of proteins, leading to an imbalance of protein availability for functions in the cell.