The molecular determinants of the aggregation and toxicity of peptides and proteins

Proteins are the building blocks of human cells and they direct the wide range of chemical reactions that are needed by a living creature. However proteins also cause a range of diseases, mostly those that affect the brains of older people, such as Alzheimer’s, Parkinson’s and motor neurone disease. In these disorders proteins stick together and become lodged in tissues, such as the brain, causing damage. We have looked at how proteins stick together in experiments that we carry out in test tubes and we have developed a computer program that can tell in advance how sticky a particular protein will be. Our recent work has shown that this program can also tell us how toxic a protein will be if it is introduced into the brain of a fruit fly. Although the fly brain is small there are many similarities with the human brain. We expect that by understanding exactly what makes a protein sticky and toxic in the fly brain we will be able to stop the same processes in the human brain. We might be able to do this by developing medicines that change the way proteins stick together to make them harmless.

This proposal brings together a group of people with a wide range of skills from the Departments of Chemistry, Physics, Nanoscience, Genetics and Medicine to investigate the fundamental causes of a range of diseases that are caused by protein misfolding and aggregation. Our project is based on three key advances that have occurred in Cambridge, the first is the understanding that the potential to form amyloid fibrils is a common, if not fundamental, property of all proteins. The second is the discovery that we can accurately predict the aggregation propensity of proteins knowing only their amino acid sequences. The third advance has been the development of Drosophila models of protein aggregation diseases. We will focus on understanding the fundamental mechanisms that underlie a range of protein misfolding disorders and use our range of skills to carefully observe protein aggregation in the test tube, interpret the data using sophisticated computer algorithms and use Drosophila model systems to provide further insights into pathological significance. We will extend our preliminary studies on the Abeta peptide and investigate other proteins implicated in neurological disorders and so formulate a quantitative model that describes the molecular determinants of peptide and protein aggregation and toxicity. Such a powerful understanding of fundamental disease mechanisms will provide us with new opportunities and strategies for therapeutic intervention.