The Structural Biology of Amyloid Aggregation

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Diseases linked with the aggregation of proteins are a major threat to today's society, especially amongst our ageing population, and the public are today acutely aware of the threats posed by these diseases, which include Alzheimer's and Parkinson's diseases and other degenerative disorders. Proteins are the workhorses of all living organisms. They perform most of the functions required for life, and their dysfunction if left unchecked by the natural defence mechanisms of cells, can be hugely damaging to cellular function and healthy life. From the moment proteins are synthesised, they exist on a knife-edge, wherein changes to their sequence can lead to aggregation and disease. One of the commonest forms of protein misfolding diseases is amyloidosis, and more than 50 different proteins are currently known to cause amyloid diseases that include both rare disorders, such as dialysis-related amyloidosis (DRA), and major societal threats such as Parkinson's disease (PD). Unfortunately we are not able prevent, treat or cure most amyloid diseases and failures of clinical trials mean that we urgently need new inspiration to fire innovative ways of tackling amyloid disease. In this three year project, we will provide new insights into the structures of amyloid fibrils and the mechanism by which they form, hopefully providing a new impetus for therapeutic ideas. The time has never been better to make this step change. By exploiting recent advances in cryo-electron microscopy (cryo-EM), we will answer three fundamentally important and medically relevant questions: (i) how diverse is the amyloid fold, and (ii) how relevant are in vitro models of amyloid aggregation to the structures formed in patients, and (iii) how can we link amyloid sequence and structure to human disease? Working closely with physicians who are expert in systemic and neurodegenerative disorders, and focussing on alpha-synuclein (involved in Parkinson's disease) and beta2-microglobulin (associated with dialysis-related and systemic amyloidoses), we will achieve these aims by determining the 3D structures of amyloid fibrils grown in vitro and comparing them with fibrils extracted from human tissue. Overall, therefore, the work will yield new insights into amyloid structure, stability and function and new understandings of how these fascinating assemblies contribute to the cellular dysfunction that may led to disease.