Quantitative approaches to defining normal and aberrant protein homeostasis

Protein homeostasis refers to the ability of cells to generate and regulate the levels of their constituent proteins in terms of conformations, interactions, concentrations and cellular localisation. We discuss here an approach in which physico-chemical properties of proteins and their environments are used to understand the underlying principles governing this process, which is crucial in all living systems. By adopting the strategy of characterising the origins of specific diseases to inform us about normal biology, we are bringing together methods and concepts from chemistry, physics, engineering, genetics and medicine. In particular, we are using a combination of in vitro, in silico and in vivo approaches to study protein homeostasis through the analysis of the effects that result from its perturbation in a select group of specific proteins, from either amino acid mutations, or changes in concentration and solubility, or interactions with other molecules. By developing a coherent and quantitative description of such phenomena, we are finding that it is possible to shed new light on how the physical and chemical properties of the cellular components can provide an understanding of the normal and aberrant behaviour of living systems. Through such an approach it is possible to provide new insights into the origin and consequences of the failure to maintain homeostasis that is associated with neurodegenerative diseases, in particular, and the phenomenon of ageing, in general, and hence provide a framework for the rational design of therapeutic approaches.