What are the structural elements of amyloids that determine their toxicity?

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Neurodegenerative diseases are characterised by the formation of insoluble deposits within the brain which are rich in amyloid fibrils arising from the misfolding of proteins. Neurodegenerative diseases are characterised by the formation of insoluble deposits within the brain which are rich in amyloid fibrils arising from the misfolding of proteins. Recent studies have revealed that the toxicity of fibrils depends on their structural properties, with different polymorphs resulting in a range of 'strains' that display varying levels of toxicity. A major challenge in characterising fibril polymorphism is the hierarchical complexity, with polymorphism exhibited at the level of monomer folding, protofibril packing and fibril assembly. At each level, differences in protein folding and packing can influence interactions with binding partners, such as the receptors expressed in neurons or immune cells, influencing the toxicity and spread of amyloid deposits within the brain. This PhD project will investigate how the environment and the presence of ex-vivo amyloid fibrils (e.g. from experimental models, cerebrospinal cord fluid or human post-mortem tissue) influences the molecular-fold and packing of higher order structures formed from amyloid-beta peptide and alpha-synuclein - the proteins implicated in Alzheimer's and Parkinson's Disease respectively. To achieve this, we will use the complementary methods of solid-state NMR, which characterises the molecular fold, and atomic force microscopy which reports on the higher-order structures formed. The toxicity of each species formed will be assessed using in-vitro neuronal and/or glial cell culture models to provide a correlate of fibril structure with progression and severity of the disease observed in patients. The formation of a given polymorph is dependent on the exact conditions employed, and to date no such systematic study correlating the hierarchical structure of the fibril with toxicity has been reported. These studies will address how variations in molecular structure guide fibril assembly and identify at which level fibril polymorphism influences the toxicity the structure exhibit. Such data will facilitate the targeting of amyloid/cell interactions, aiding the management of neurodegenerative diseases.