Exploring the roles of a novel prion-like protein in stress resistance and ageing

Ageing is associated with increased rates of disease, including neurodegenerative conditions. Prion-like proteins (PrLPs) play major roles in age-associated neurodegeneration, but their physiological functions are often poorly understood. Defining these functions would increase our understanding of the behaviour and importance of PrLPs, and how and why they become dysregulated with age. This is critical to understanding the key roles they play in age-related neurodegeneration.

We recently characterized an unstudied PrLP in C. elegans that scores highly for prion-like amino acid composition. This protein is essential for resistance to stress and pathogens, and localises to lysosomes. As lysosomes play key roles in stress responses and ageing, we want to understand this protein's functions at the lysosome, to define a novel role for PrLPs in determining stress resistance through effects on lysosome function. This project will comprehensively examine the roles of this novel PrLP by:

1) Defining its roles in lysosome activity, localisation and dynamics 2) Establishing the contribution of its domains to these roles 3) Determining its involvement in pathways that promote healthy ageing

In addition, we will collaborate with the lab of Prof. Tom Wileman to determine the conservation of these mechanisms in mammalian cells. Through these approaches, we will expand our knowledge of the roles and regulation of PrLPs in vivo, providing critical insight into how these proteins become dysregulated with age.

We will also increase our understanding of the roles and importance of lysosome regulation in stress resistance and ageing, identifying novel roles played by PrLPs and lysosomes in the ageing process and in anti-ageing interventions. These insights may ultimately lead to the identification of new targets for the development of therapies for ageing and age-related disease.