Eco-evolutionary tradeoffs in the dynamics of prion strain competition

TL;DR

This paper investigates how prion strains evolve and compete within and between cells, revealing tradeoffs that influence their stability, transmission, and coexistence, using mathematical modeling of the nucleated polymerization process.

Contribution

It introduces a model showing how prion fragmentation rates evolve to balance reproduction and stability, and explores eco-evolutionary tradeoffs affecting strain coexistence.

Findings

Fragmentation rates evolve to an evolutionarily stable value.

Evolved fragmentation rate differs from the rate optimizing transmission.

Coexistence of strains is favored by eco-evolutionary tradeoffs.

Abstract

Prion and prion-like molecules are a type of self replicating aggregate protein that have been implicated in a variety of neurodegenerative diseases. Over recent decades the molecular dynamics of prions have been characterized both empirically and through mathematical models, providing insights into the epidemiology of prion diseases, and the impact of prions on the evolution of cellular processes. At the same time, a variety of evidence indicates that prions are themselves capable of a form of evolution, in which changes to their structure that impact their rate of growth or fragmentation are replicated, making such changes subject to natural selection. Here we study the role of such selection in shaping the characteristics of prions under the nucleated polymerization model (NPM). We show that fragmentation rates evolve to an evolutionary stable value which balances rapid reproduction of $PrP^{Sc}$ aggregates with the need to produce stable polymers. We further show that this evolved fragmentation rate differs in general from the rate that optimizes transmission between cells. We find that under the NPM, prions that are both evolutionary stable and optimized for transmission have a characteristic length of $3n$, i.e three times the critical length below which they become unstable. Finally we study the dynamics of inter-cellular competition between strains, and show that the eco-evolutionary tradeoff between intra- and inter-cellular competition favors coexistence.