A unifying model for the propagation of prion proteins in yeast brings insight into the [PSI+] prion.

Paul Lemarre,Suzanne S. Sindi,Laurent Pujo-Menjouet,Philip K Maini

doi:10.1371/journal.pcbi.1007647

Abstract

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.

Highlights

Amyloids are self-perpetuating protein aggregates, involved in many neurodegenerative diseases in mammals such as Alzheimer’s Disease, Parkinsons’s Disease, Creutzfeldt-Jakob Disease, Huntington’s Disease [1]
The propagation of yeast prions is a multi-scale system where molecular processes are coupled to cellular processes such as cell growth and division to produce effects that are observable at the phenotypical scale, i.e. at the scale of colonies
We propose a novel approach based on the use of impulsive differential equations

Summary

Introduction

Amyloids are self-perpetuating protein aggregates, involved in many neurodegenerative diseases in mammals such as Alzheimer’s Disease, Parkinsons’s Disease, Creutzfeldt-Jakob Disease, Huntington’s Disease [1]. Native yeast prions share many specificities with mammalian prions [4], and the protein quality control machinery involved in their propagation is highly conserved between mammals and yeast. Yeast models are used to screen for anti-amyloid drugs through the artificial expression of mammalian proteins [5]. Many kinetic models of aggregate growth and nucleation have been proposed [6], but their validation using data from yeast colonies is challenging. The propagation of yeast prions is a multi-scale system where molecular processes are coupled to cellular processes such as cell growth and division to produce effects that are observable at the phenotypical scale, i.e. at the scale of colonies. It is important to emphasize that this framework is versatile and can be used to study the evolution of any chemically active intracellular components through mass-action kinetics inside growing yeast colonies

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