Suicidal [PSI+] is a lethal yeast prion.
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ABSTRACT:
SUBMITTER: McGlinchey RP
PROVIDER: S-EPMC3069153 | biostudies-other | 2011 Mar
REPOSITORIES: biostudies-other
Publications
Suicidal [PSI+] is a lethal yeast prion.
McGlinchey Ryan P RP Kryndushkin Dmitry D Wickner Reed B RB
Proceedings of the National Academy of Sciences of the United States of America 20110314 13
[PSI(+)] is a prion of the essential translation termination factor Sup35p. Although mammalian prion infections are uniformly fatal, commonly studied [PSI(+)] variants do not impair growth, leading to suggestions that [PSI(+)] may protect against stress conditions. We report here that over half of [PSI(+)] variants are sick or lethal. These "killer [PSI(+)]s" are compatible with cell growth only when also expressing minimal Sup35C, lacking the N-terminal prion domain. The severe detriment of kil ...[more]
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Project description:The use of yeast systems to study the propagation of prions and amyloids has emerged as a crucial aspect of the global endeavor to understand those mechanisms. Yeast prion systems are intrinsically multi-scale: the molecular chemical processes are indeed coupled to the cellular processes of cell growth and division to influence phenotypical traits, observable at the scale of colonies. We introduce a novel modeling framework to tackle this difficulty using impulsive differential equations. We apply this approach to the [PSI+] yeast prion, which is associated with the misconformation and aggregation of Sup35. We build a model that reproduces and unifies previously conflicting experimental observations on [PSI+] and thus sheds light onto characteristics of the intracellular molecular processes driving aggregate replication. In particular our model uncovers a kinetic barrier for aggregate replication at low densities, meaning the change between prion or prion-free phenotype is a bi-stable transition. This result is based on the study of prion curing experiments, as well as the phenomenon of colony sectoring, a phenotype which is often ignored in experimental assays and has never been modeled. Furthermore, our results provide further insight into the effect of guanidine hydrochloride (GdnHCl) on Sup35 aggregates. To qualitatively reproduce the GdnHCl curing experiment, aggregate replication must not be completely inhibited, which suggests the existence of a mechanism different than Hsp104-mediated fragmentation. Those results are promising for further development of the [PSI+] model, but also for extending the use of this novel framework to other yeast prion or amyloid systems.
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