Support for a Wellcome Trust/Academy of Medical Sciences Internship (360G-Wellcome-096685_Z_11_A)

A large number of human diseases are associated with the deposition of amyloid-like aggregates. As amyloid species associated with different diseasesshare structural properties, it is hypothesised a generic mechanism of cytotoxicity may be the underlying cause for many different diseases pathology. The projects key goals are; 1) Elucidate structural information on amyloid fibril ends Ends of fibrils have been shown to interact with synthetic membranes, and so elucidating the structure of fibril ends may provide insights into mechanism of interaction, which may be a pathway of fibril cytotoxicity. 2) Analyse how amyloid fibrils interact with membrane fractions of cells As fibrils have been shown to interact with synthetic membranes, we seek to analyse how they interact with membranes extracted from the cell such as lysosomal membranes. 3) Assess the structure of amyloid in the cellular environment and characterise the cell's response. We aim to image both fibrils and oligomers inside whole cells using high resolution imaging techniques including cryo-electron tomography, in order to characterise how the cell responds to amyloid exposure. These goals will help to elucidate underlying mechanisms of amyloid cytotoxicity, providing insights into the pathology of diseases such as Alzheimer's disease, Parkinson's disease and haemodialysis related amyloidosis.