Bioscience for an integrated understanding of health

Category: Standard Studentships

Does the structure of amyloid determine the rate of neuronal cell loss?

Primary Supervisor

Dr Philip T.F. Williamson – University of Southampton


Dr Wei-Feng Xue – University of Kent

Professor Jessica Teeling – University of Southampton


Neurodegenerative diseases are characterised by the deposition of amyloid fibrils within the brain.

The fibrils are composed of proteins in the amyloid state that exhibit significant polymorphism resulting in a multitude of strains that display varying levels of toxicity. A major challenge associated with characterising fibril polymorphism is the hierarchical complexity in fibril assembly, with polymorphism exhibited at the level of monomer folding, protofibril packing and fibril assembly. At each level, differences in folding and packing can influence interactions with binding partners, including neuronal cell surface receptors, which in turn can influence fibril stability and the progression of the deposits through the brain.

In these studies, we propose to investigate how the environment and the presence of ex-vivo seeds (e.g. obtained 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 highly complementary methods of solid-state NMR (SS-NMR), which can provide insights into the molecular fold, and atomic force microscopy (AFM) which can report on the high-order structures formed. The toxicity of each species formed will be assessed using in-vitro neuronal 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 highly 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 is invaluable in understanding how to target amyloid/cell interactions for the management of neurodegenerative diseases.