Quantitative approaches to defining normal and aberrant protein homeostasis

Lead Research Organisation: University of Cambridge
Department Name: Chemistry

Abstract

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.

Technical Summary

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.

Publications

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Arosio P (2014) Chemical kinetics for drug discovery to combat protein aggregation diseases. in Trends in pharmacological sciences

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Baldwin AJ (2011) Metastability of native proteins and the phenomenon of amyloid formation. in Journal of the American Chemical Society

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Buell AK (2011) Population of nonnative states of lysozyme variants drives amyloid fibril formation. in Journal of the American Chemical Society

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Buell AK (2014) Solution conditions determine the relative importance of nucleation and growth processes in a-synuclein aggregation. in Proceedings of the National Academy of Sciences of the United States of America

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Chen SW (2015) Structural characterization of toxic oligomers that are kinetically trapped during a-synuclein fibril formation. in Proceedings of the National Academy of Sciences of the United States of America

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Ciryam P (2013) In vivo translation rates can substantially delay the cotranslational folding of the Escherichia coli cytosolic proteome. in Proceedings of the National Academy of Sciences of the United States of America

 
Description We have investigated the fundamental biophysical principles of protein homeostasis. Most notably, we have developed a chemical kinetics theory of protein aggregation and demonstrated that it can be used to develop innovative drug discovery strategies.
Exploitation Route The drug discovery programme that we established following our discoveries are starting provide the first compounds with therapeutic activity against Alzheimer's and Parkinson's diseases.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description Our research into the biophysical principles of protein homeostasis have opened the way to the development of a range of new methods for the characterisation of protein aggregation. In particular, the theory of chemical kinetics of protein aggregation is transforming the way in which this phenomenon can be studied and controlled in a quantitative manner by using small molecules, antibodies and molecular chaperones.
First Year Of Impact 2012
Sector Chemicals,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal,Economic

 
Description Elan Pharmaceuticals
Amount £20,000,000 (GBP)
Organisation Perrigo 
Department Elan Pharmaceuticals
Sector Private
Country Ireland
Start 01/2012 
End 09/2021
 
Title Small molecules against aggregation 
Description We have developed a series of small molecules against protein aggregation. In particular, we have discovered a compound, called '228', which inhibits the toxicity of alpha-synuclein aggregates in an animal model of Parkinson's disease 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact The '228' compound is the first in our pipeline of drug discovery for neurodegeneration. 
 
Description Elan Pharmaceuticals 
Organisation Perrigo
Department Elan Pharmaceuticals
Country Ireland 
Sector Private 
PI Contribution We have collaborated on a drug discovery project for Alzheimer's and Parkinson's diseases with Elan, contributing our biophysical methods for the characterisation of the aggregation process of protein and peptides.
Collaborator Contribution Elan Pharmaceuticals has been at the forefront of research in drug discovery for neurodegenerative diseases in the past 20 years. They have contributed to our programme with their expertise in drug development.
Impact We have developed a compound, called '228', which has shown to be effective in reducing the toxicity of alpha-synuclein aggregates in animal models.