Cryo-EM studies of amyloid fibrils and their mechanisms of formation in vitro and in vivo

Amyloidosis is a pathological condition associated with the aggregation of proteins into fibrils, and is the underlying pathology in diseases such as Alzheimer’s and Parkinsons diseases. Despite the importance of this process to diseases that shape today’s society, therapies remain remote.

In this project we will use state of the art imaging technologies to gain fundamental biological insight. Specifically, we will use the Titan Krios cryo-EM microscopes in Leeds to determine the structure of amyloid fibrils formed from the protein 2-microglobulin and natural variants which cause enhanced amyloid disease. Using biochemical and biophysical assays, combined with cryo-EM, we will determine how amyloid fibrils form and how they bind essential cellular components including molecular chaperones. Finally, you will use cell biology, super resolution imaging and cryo-ET and cryo X-ray tomography to examine fibril formation within living cells.

Overall, therefore, the aim is to provide new mechanistic insights into fibril structure and fibril-induced cellular disruption by exploiting modern cryo-EM to the full.

For more information about the Radford group and for recent publications please see http://www.astbury.leeds.ac.uk.