Exploring the de novo Establishment of [PSI+] Prion Variants and the Role of a Heterologous Prion
thesisposted on 2013-06-28, 00:00 authored by Jaya Sharma
Prions are infectious proteins, which cause severly fatal neurodegenerative diseases in mammals and are heritable traits in fungi. In mammals, the prion protein, PrP can exist in more than one conformations and surprisingly, these conformations composed of one primary sequence can cause neurodegenerative diseases of distinct pathologies. Despite the dissimilarity in genetic sequences, mammalian and yeast prions both share certain characteristics like protein-only transmission and common biophysical and biochemical properties. Moreover, some of the yeast prions are shown to exist in more than one conformations and these are associated with distinct phenotypes called as prion variants. Studies have further established that they are analogous to mammalian prion strains. We showed that, yeast prion protein, Sup35, can misfold into more than one conformations in a single host cell during prion induction. These multiple conformations are then inherited among progeny exhibiting distinct phenotypes or variants. These prion variants either can mature into one in daughter generations or remain unspecified indefinitely as we discovered in a novel [PSI+] variant, unspecified [PSI+]. We also investigated, how the presence of variants of pre-existing prion, [PIN+], differentially affects the appearance of heterologous prion, [PSI+]. We showed, [PIN+] variants have specific preference to cross-seed certain variants of [PSI+] suggestive of their favourable interaction and structural analogy. [PIN+] variants have different number of propagons/seeds, however it is not in accordance to their [PSI+] seeding efficiency. Finally, we showed [PIN+] variants do not differ in the level of immunocaptured level of Rnq1 by Sup35 during [PSI+] induction. These suggest the difference in the cross-seeding efficiency of [PIN+] variants is conformation dependent and it comes into play following binding during [PSI+] induction stage.