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 of diseases such as Alzheimer’s and Parkinson’s diseases. Despite the increasing importance of amyloid diseases in today’s ageing population, therapies remain remote.

In this project we will use state of the art imaging technologies to gain fundamental insights into the structure of amyloid fibrils, how they form and how they interact with cellular components. Specifically, using powerful Titan Krios electron microscopes recently installed in the Astbury Centre for Structural Molecular Biology at Leeds we will use cryo-EM 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-electron microscopy, we will also determine the structure of amyloid assembly intermediates and examine how they bind essential cellular components including molecular chaperones. Finally, we will use cell biology, super resolution imaging, cryo-electron tomography and cryo X-ray tomography to examine fibril formation within living cells.

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



More details about research in our research groups can be found at:
http://bmbsgi10.leeds.ac.uk
http://www.astbury.leeds.ac.uk.

Please contact [Email Address Removed] for more information.