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Capturing how Hsp90 prevents the formation of cell-disruptive toxic amyloid species by Cryo-EM in a C. elegans model for Alzheimer’s Disease

Project Description

Stress and aging challenge the health of a proteome and increase susceptibility to protein conformational diseases, a hallmark of many neurodegenerative diseases, including Alzheimer’s Disease. But how and when do amyloid proteins exert their toxic effect to cells that lead to disease in an organism? And how can we prevent their formation? This project addresses both these questions by combining biochemical and structural biology methods with high-resolution Cryo-EM imaging of the toxic species formed in an in vivo Alzheimer’s disease model. Using a C. elegans Alzheimer’s Disease model, our lab has recently shown that activation of Hsp90 expression prevents the formation of toxic amyloid protein deposits in the animal throughout aging (O’Brien et al, Cell Reports 2018). The student will image the progression of amyloid aggregates as the animal ages and correlate A fibril formation with cytotoxicity. Aggregates formed in vitro and ex vivo will be analysed to understand their interaction with Hsp90 and their cellular toxicity analysed in combination with gaining high resolution structures by Cryo-EM.

The student will gain highly interdisciplinary training that combines the novelty and high-resolution power of Cryo-EM with capturing toxic species in an in vivo model of Alzheimer’s disease, using C. elegans as a model system.

Please see following links for more information:

Twitter: @HawleLab

Funding Notes

White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology
4 year fully-funded programme of integrated research and skills training, starting Oct 2019:
• Research Council Stipend
• UK/EU Tuition Fees
• Conference allowance
• Research Costs

At least a 2:1 honours degree or equivalent. We welcome students with backgrounds in biological, chemical or physical sciences, or mathematical backgrounds with an interest in biological questions.
EU candidates require 3 years of UK residency in order to receive full studentship

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process.

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Daniel O’Brien* and van Oosten-Hawle,P. (2016). Regulation of cell nonautonomous proteostasis in metazoans. Essays in Biochemistry. 2016 Oct 15;60(2):133-142.
*post graduate co-author.

Tipping KW; van Oosten-Hawle P; Hewitt EW; Radford SE (2015). Amyloid fibres: inert end-stage aggregates or key players in disease? Trends in Biochemical Sciences, 2015. 40 (12):719-27

van Oosten-Hawle P, Morimoto RI. 2014. Organismal Proteostasis: role of cell nonautonomous regulation and intertissue stress signaling. Genes & Development. 2014 Jul 15; 28(14):1533-1543.

van Oosten-Hawle P, Porter RS, Morimoto RI. Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153:1366-78

Wieteska, L., Shahidi, S., Zhuravleva A. (2017) Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation. eLife (In Press).

Zhuravleva*, A.; Gierasch*, L.M. (2015). Substrate-binding domain conformational dynamics mediate Hsp70 allostery. Proc Natl Acad Sci USA 112, E2865-E2873 (*corresponding authors)

Zhuravleva, A., Clérico, E. M., and Gierasch, L. M. (2012). An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151, 1296-1307

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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