Modelling yeast prion dynamics in the living cell

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The last decade has seen a new challenge to the dogma that inheritance is based exclusively on DNA. This has come in part from the discovery of prions in yeast and other fungi. Historically, prions have been intensively studied in relation to their ability to cause diseases such as 'Mad Cow Disease' and the human form, Creutzfeldt-Jakob Disease (CJD). However the discovery of prions in fungi that can potentially be of benefit to the host organism suggests that prions may actually represent an entirely new form of protein-based heredity. One such prion-based 'epigenetic' determinant in Baker's Yeast (Saccharomyces cerevisiae) will be studied in this project; the so-called [PSI+] prion. This prion can significantly alter the way that the yeast cell responds to certain toxic chemicals for example. The approach we are planning to take is a novel one, integrating biological experiments with mathematical modelling to study the behaviour of prions in a living yeast cell. This is an approach we first developed on a previous BBSRC-funded project and this new project builds on that, broadening the approach to model the process by which prions are replicated in an asymmetrically dividing yeast cell. Our long-term goal is to understand fully the molecular details of exactly how prions are so effectively generated and then passed on to other yeast cells. We already know that this requires cells to produce prion 'seeds' which can be passed from the mother cell to the daughter cell (a process we refer to as prion transmission). These seeds - which we refer to as propagons - are generated by breaking up much larger aggregated forms of the prion protein that are found in yeast cells. By employing a multidisciplinary approach we aim to establish the mechanism that operates in the growing yeast cell to ensure that new prion seeds are efficiently generated and transmitted to a new daughter cell. The research project will be built upon an iterative process of model improvement through biological experiments conducted to allow estimation of model parameters and then assessment of the adequacy of the new models that emerge. This approach will provide us, for example, with the ability to assess and ultimately predict the way in which changes in the cell's make up or function may impact on prion replication and/or transmission. The outcome will be a new understanding of how this important class of 'epigenetic' elements - some 20 of which have now been described - are replicated in the living cell, and how that process can be perturbed. The findings will guide future studies on the processes both in fungi and in mammals. A longer term outcome of the research will be identifying components of the cell that can be targeted by new drugs to block the generation and/or transmission of prion seeds.