The suprastructure-function relationship between amyloid assemblies and their toxic and infectious potentials

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A number of human disorders, for example Alzheimer's disease (AD), Parkinson's disease (PD), and transmissible spongiform encephalopathies (TSEs), are associated with the abnormal folding and assembly of proteins. The net result of this misfolding is the formation of large insoluble protein deposits as well as toxic and transmissible protein particles in a state called amyloid. Not all amyloids are associated with disease, as some are tolerated by the cells or even perform beneficial functions for their host organisms. Why some amyloid are disease-associated and toxic while others are not is a fundamentally important biological question that we currently do have answer to. This gap in our knowledge not only prevents researchers from fully understanding the fundamental biology in the amyloid life-cycle, but also prevent pharmaceutical industries from targeting the correct molecular structures and developing effective therapeutics against the devastating amyloid associated diseases. In this project, we will address this knowledge gap by investigating the new idea that whether amyloid is associated with pathology or not is linked to how individual amyloid filaments, as building blocks, are organised to form large structures in the range of a millionth to a billionth of metre in size, which we call the amyloid suprastructure.Recently, detailed atomic-resolution structural models for several disease-associated amyloid fibrils resolved using solid-state nuclear magnetic resonance spectroscopy and transmission electron microscopy methods have allowed insight into how individual atoms are organised in the amyloid structures. Using these methodologies have resolved the detailed organisation of individual protein chains in amyloid structures, yet how these structures interact with biology and why some amyloid are associated with disease even though all amyloid share the same type of organisation of the protein chains has not been understood. Here, we propose that the "missing-link" between our knowledge on amyloid structures and how they interact with biology and/or associated with disease is encoded in the type of suprastructure individual amyloid filaments will assembly into, that is whether these amyloid building-blocks may form straight bundles, twisted ropes or tubes, large open networks or tightly packed clusters etc. If we can gather data on the types of suprastructures amyloid building-blocks can form and follow how each of these structures may influence how amyloid interact with cells and propagate in a disease context, then we will be able to resolve the missing-link between amyloid structure and their biology. This is exactly what we can now do, as we will use atomic force microscopy (AFM) imaging method that enable us to visualise large number of individual amyloid superstructures that are between millionths of metre in size to billionths of metre in size, so called mesoscopic size range. Atomic force microscopy imaging of amyloid structures in these intermediate length scales between the sizes of atoms to the size of cells gives low-noise and high resolution images that are very much ideal for the precise quantitative measurement of individual amyloid suprastructures in sample that are composed of mixtures of diverse assemblies such as amyloid samples. This combined with biological measurements of how the same amyloid structures behave with/in cells, we will be uniquely placed to discover the missing-link between structure of amyloid and their cellular functions. Our findings will shed new light on the why amyloid structures can confers cytotoxicity and infectivity in mammals and humans in some but not all cases, and will also give us clues as to what pharmaceutical industries should target in the search for effective therapies against the devastating diseases some amyloid structures are associated with.