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An integrated approach to the study of cellular interactions with amyloid


Project Description

The formation of insoluble amyloid fibrils is associated with a spectrum of human disorders, the amyloidoses, which include Alzheimer’s, Parkinson’s, type 2 diabetes and dialysis related amyloidosis (DRA). In these disorders the formation of amyloid fibrils is associated with cellular dysfunction and tissue destruction. Yet despite decades of research the culprit species and mechanisms of amyloid toxicity remain poorly understood.

Our goal is to determine how the structure and physical properties of amyloid affects cellular physiology and viability. This involves a multidisciplinary approach in which information obtained by NMR, atomic force microscopy, electron microscopy, photo-crosslinking, mass spectrometry and fluorescence based spectroscopic techniques is integrated with analyses of cell function and viability. We are studying the oligomeric assembly intermediates, fibrils and fibril-derived oligomers formed by an array of amyloidogenic precursors, including α-synuclein (Parkinson’s), amyloid-β (Alzheimer’s) and β2-microglobulin (DRA). Experimental approaches used to analyse the interactions and effects of these amyloid species on cells include plate-based assays for cell viability and metabolism, live cell confocal microscopy microscopy, flow cytometry, subcellular fractionation and proteomics. In addition, we are exploring approaches for the delivery of amyloid aggregates into the cytoplasm of single cells with colleagues in the School of Electrical and Electronic Engineering.

Funding Notes

Self-funded students: International or domestic self-funded or scholarship/fellowship PhD students are always welcome to apply. International students must have a good command of both written and spoken English. In addition to University fees, laboratory fees will be required if you are self-funded. Applications can be made throughout the year.

References

The project builds upon a successful collaboration between Dr Eric Hewitt and Professor Sheena Radford. Below are some of their recent publications that are relevant to this project.

Xue, WF, Hellewell, AL, Gosal, WS, Homans, SW, Hewitt, EW, Radford, SE (2009) Fibril fragmentation enhances amyloid toxicity. J. Biol Chem. 284, 34272-82

Porter MY, Routledge KE, Radford SE, Hewitt EW. (2011). Characterization of the response of primary cells relevant to dialysis-related amyloidosis to β2-microglobulin monomer and fibrils.PLoS One. 6:e27353.

Goodchild SC, Sheynis T, Thompson R, Tipping KW, Xue WF, Ranson NA, Beales PA, Hewitt EW, Radford SE. (2014) β2-Microglobulin amyloid fibril-induced membrane disruption is enhanced by endosomal lipids and acidic pH. PLoS One. 9, e104492.

Jakhria, T, Hellewell, AL, Porter, MY, Jackson, M, Tipping, KW, Xue, WF Radford, SE, Hewitt, EW (2014). β2-microglobulin amyloid fibrils are nanoparticles that disrupt
lysosomal membrane protein trafficking and inhibit protein degradation by lysosomes. J. Biol. Chem. 289, 35781-94

Tipping KW, Karamanos TK, Jakhria T, Iadanza MG, Goodchild SC, Tuma R, Ranson NA, Hewitt EW, Radford SE. (2015). pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. Proc Natl Acad Sci U S A. 112:5691-6.

Tipping KW, van Oosten-Hawle P, Hewitt EW and Radford, SE. (2015) Amyloid Fibres: Inert End-Stage Aggregates or Key Players in Disease? Trends in Biochemical Sciences 40, 719-727

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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