Quantitative approaches to defining normal and aberrant protein homeostasis

The ability of all living systems to function requires a high level of regulation of the behaviour of proteins, which are the molecules that are involved in essentially all the biochemical reactions taking place within them. Proteins usually carry out their functions by adopting specific conformations, known as native states, which are encoded in their amino acid sequences. Much research in molecular biology has therefore been focused on the properties of native states of proteins. It is increasingly evident, however, that non-native states of proteins also play a fundamental role in determining the normal development of cellular activities. A variety of diseases, which include systemic conditions such as type II diabetes and dialysis-related amyloidosis, and neurodegenerative conditions such as Alzheimer's, Parkinson's and the various prion diseases, have been identified that are associated with the incorrect folding of proteins and their subsequent aggregation. Very considerable efforts, including much work by our own research groups, have been devoted in the last several years to addressing these problems by enhancing our ability of understanding the behaviour of proteins, including folding, misfolding and assembly. The approach that we propose in this application is based on two realisations. The first is that the investigation of protein homeostasis provides a general framework to formulate a comprehensive description of the behaviour of proteins in the cell. The second is that major advances can now be made by exploiting the opportunities offered by technical and conceptual developments that have taken place in disciplines such nanoscience, chemistry and neurobiology. We have thus brought together researchers from these disciplines that have already an established track record of successful collaborations to put forward an ambitious programme or research with the goal of increasing the level at which we can understand rationally and quantitatively the outcome of cellular processes. More specifically, we propose to carry out research at the Department of Chemistry (Prof Dobson and Dr Vendruscolo) to achieve a detailed determination, by a combination of experiment and theory, of the multiple possible states of proteins, including partially folded conformations, misfolding intermediates, amyloid fibrils, as well as of the pathways of their interconversion. The activity at the Nanoscience Centre (Prof Welland) will be devoted to the use of nanoscience techniques to establish quantitative relationships between different aspects of protein behaviour, including their aggregation rates and the mechanical properties of amyloid structures. Finally, at the Departments of Genetics (Dr. Crowther) and of Medicine (Prof Lomas) we will use in vivo Drosophila models in conjunction with theoretical predictions to enhance our understanding of the physico-chemical origin of misfolding diseases and to explore the development of rational strategies for their treatment.

Cellular homeostasis depends on the presence of sophisticated quality control mechanisms that regulate the behaviour of proteins in their native and non-native states. A variety of diseases, which include systemic disorders such as type II diabetes and dialysis-related amyloidosis, and neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, have been identified as being associated with incorrect processing of proteins in the cell. In this application we formulate a strategy for describing and potentially altering the behaviour of protein molecules in the cell, including their folding, misfolding and aggregation, based on a quantitative understanding of protein homeostasis. Our approach is based on the exploitation of the opportunities offered by technical developments in disciplines such as physics, nanoscience, chemistry and neurobiology. We have thus brought together researchers from such disciplines that have already an established track record of successful collaborations to put forward an ambitious programme to increase the level at which we can understand quantitatively cellular processes. The research at the Department of Chemistry will aim at the determination by a combination of experiment (Prof Dobson) and theory (Dr Vendruscolo) of multiple states of proteins, including partially folded conformations, misfolding intermediates, amyloid fibrils, and of the pathways of their interconversion. The activity at the Nanoscience Centre (Prof Welland) will involve the use of nanoscience techniques to establish quantitative relationships among different properties of proteins, including their aggregation rates and the mechanical properties of amyloids. At the Deparments of Genetics (Dr.Crowther) and of Medicine (Prof Lomas) we will use Drosophila models in conjunction with theoretical predictions to enhance our understanding of the origins of misfolding diseases and to explore the development of rational strategies for their treatment.