[PSI+] prion variant establishment in yeast

Summary Differences in the clinical pathology of mammalian prion diseases reflect distinct heritable conformations of aggregated PrP proteins, called prion strains. Here, using the yeast [PSI+] prion, we examine the de novo establishment of prion strains (called variants in yeast). The [PSI+] prion protein, Sup35, is efficiently induced to take on numerous prion variant conformations following transient overexpression of Sup35 in the presence of another prion, e.g. [PIN+]. One hypothesis is that the first [PSI+] prion seed to arise in a cell causes propagation of only that seed's variant, but that different variants could be initiated in different cells. However, we now show that even within a single cell, Sup35 retains the potential to fold into more than one variant type. When individual cells segregating different [PSI+] variants were followed in pedigrees, establishment of a single variant phenotype generally occurred in daughters, granddaughters or great-granddaughters – but in 5% of the pedigrees cells continued to segregate multiple variants indefinitely. The data are consistent with the idea that many newly formed prions go through a maturation phase before they reach a single specific variant conformation. These findings may be relevant to mammalian PrP prion strain establishment and adaptation.