Generalizing a mathematical model of prion aggregation allows strain coexistence and co-stability by including a novel misfolded species

Abstract

Prions are proteins capable of adopting misfolded conformations and transmitting these conformations to other normally folded proteins. Prions are most commonly known for causing fatal neurodegenerative diseases in mammals but are also associated with several harmless phenotypes in yeast. A distinct feature of prion propagation is the existence of different phenotypical variants, called strains. It is widely accepted that these strains correspond to different conformational states of the protein, but the mechanisms driving their interactions remain poorly understood. This study uses mathematical modeling to provide insight into this problem. We show that the classical model of prion dynamics allows at most one conformational strain to stably propagate. In order to conform to biological observations of strain coexistence and co-stability, we develop an extension of the classical model by introducing a novel prion species consistent with biological studies. Qualitative analysis of this model reveals a new variety of behavior. Indeed, it allows for stable coexistence of different strains in a wide parameter range, and it also introduces intricate initial condition dependency. These new behaviors are consistent with experimental observations of prions in both mammals and yeast. As such, our model provides a valuable tool for investigating the underlying mechanisms of prion propagation and the link between prion strains and strain specific phenotypes. The consideration of a novel prion species brings a change in perspective on prion biology and we use our model to generate hypotheses about prion infectivity.