A structured model and likelihood approach to estimate yeast prion propagon replication rates and their asymmetric transmission.

Abstract

Prion proteins cause a variety of fatal neurodegenerative diseases in mammals but are generally harmless to Baker's yeast (Saccharomyces cerevisiae). This makes yeast an ideal model organism for investigating the protein dynamics associated with these diseases. The rate of disease onset is related to both the replication and transmission kinetics of propagons, the transmissible agents of prion diseases. Determining the kinetic parameters of propagon replication in yeast is complicated because the number of propagons in an individual cell depends on the intracellular replication dynamics and the asymmetric division of yeast cells within a growing yeast cell colony. We present a structured population model describing the distribution and replication of prion propagons in an actively dividing population of yeast cells. We then develop a likelihood approach for estimating the propagon replication rate and their transmission bias during cell division. We first demonstrate our ability to correctly recover known kinetic parameters from simulated data, then we apply our likelihood approach to estimate the kinetic parameters for six yeast prion variants using propagon recovery data. We find that, under our modeling framework, all variants are best described by a model with an asymmetric transmission bias. This demonstrates the strength of our framework over previous formulations assuming equal partitioning of intracellular constituents during cell division.