Award details

Prion protein misfolding the structural biology of prion diseases

Reference	BB/D005027/1
Principal Investigator / Supervisor	Dr John Viles
Co-Investigators / Co-Supervisors	Professor David Brown, Dr Stephen Rigby
Institution	Queen Mary University of London
Department	Sch of Biological and Chemical Sciences
Funding type	Research
Value (£)	377,146
Status	Completed
Type	Research Grant
Start date	01/06/2006
End date	28/02/2010
Duration	45 months

Abstract

The prion protein (PrP) is a Cu(II) binding cell surface glyco-protein. Misfolding of PrP into a b-sheet rich conformation is responsible for neurodegenerative diseases such as CJD in humans and BSE (mad cow disease) in cattle. We propose to study the structure and misfolding of PrPC, in particular the copper loaded forms of PrP. Copper bound forms of PrP are physiologically relevant and those studying the folding and fibrillisation of PrP should certainly consider the effect of Cu(II) ions on the biophysical properties of PrPC. We will use a range of spectroscopic and biophysical techniques to investigate how Cu(II) ions influence the structure and fibrillisation of PrP. In particular, we will use NMR, CD and EPR for which we have proven experience. For example, 15N HSQC NMR data will be used to monitor misfolding and backbone dynamics of PrP. Ni(II) will be used as a diamagnetic replacement ion to probe the effect of metal binding to PrP by NMR methods. CD will be used to monitor the folding transitions and stability of PrP when exposed to changes in solvent environment and in the presence of Cu(II) ions. Visible-CD and complementary Cu-EPR and ESEEM will be used to study the coordination geometry of the Cu(II) complexes formed. The studies will use various recombinant and synthetic fragments of the prion protein. The proposal represents a step towards understanding the misfolding processes of the prion protein.

Summary

The proposal would fund two research workers for 3 years to address fundamental molecular processes associated with Prion diseases, which include CJD in humans and mad-cow disease in cattle. A key feature of this fatal neurodegenerative disease is the accumulation of a small molecule, the prion protein within the brain. The prion protein changes shape in the diseased form and then clumps together to form the insoluble plaques found in the brains of patients with prion disease. It is the ability of the prion protein to change shape and misfold that will be studied. The interaction of the prion protein with physiological levels of the essential mineral copper will also be investigated, looking into how for example copper influences the shape (structure) and misfolding of the prion protein. These studies will inform drug design and assist in the development of medicines for the disease. Prion diseases have similarities with the more prevalent neurodegenerative disease Alzheimer's and knowledge gained in this study will increase our understanding of both diseases.

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	Animal Health, Structural Biology, TSEs (transmissible spongiform encephalopathies)
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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