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The role of prion protein isoforms as determinants of TSE susceptibility

Reference	BBS/E/R/00001815
Principal Investigator / Supervisor	Dr Wilfred Goldmann
Co-Investigators / Co-Supervisors
Institution	The Roslin Institute
Department	The Roslin Institute Department
Funding type	Research
Value (£)	6,450
Status	Completed
Type	Institute Project
Start date	01/04/2007
End date	30/09/2010
Duration	42 months

Abstract

During prion disease formation, the normal protein (PrPC) is converted into the disease form (PrPSC) through an unknown mechanism. PrPC is then used as a substrate for the conversion of more PrPSC. Independent of disease; PrPC is proteolytically cleaved into various isoforms. One of these cleavage events occurs between codons 112 and 113 of ovine PrP and results in two fragments of 9kDa and 18kDa, called N1 and C1. The function of the N1/C1 isoforms and their relevance to disease remains to be studied. The C1 peptide is shorter than PrPSC and we assume that C1 does not take part in the conversion process. The reduction of full length PrP protein by proteolytic processing may therefore influence either the rate of PrPSC production in disease or the rate of PrPC recycling in the normal cell. This project aims to investigate (I) the variation in the ratio between full length PrPC and the C1 isoform in ovine cells and tissues and (II) the possible differences of this ratio between genotypes and age groups. Our aim is to show whether there is an association between cleavage ratios of full length PrP and the C1 peptide and susceptibility to scrapie disease. Using monoclonal antibody 6H4 in western blotting we have detected full length PrP and cleavage product C1 in the cortex region of the brain for ovine genotypes with varying degrees of susceptibility to prion disease, eg ARR/ARR versus VRQ/VRQ. Analysis of the ratios has been carried out by densitometry. We have also dissected four regions of the sheep brain and repeated ratio measurements between full length PrP and C1. We could show significant differences of C1 levels in these areas. Brain tissues from animals of different ages (new born, lambs and adult) were also tested for any differences.

Summary

unavailable

Committee	Closed Committee - Agri-food (AF)
Research Topics	Animal Health, Neuroscience and Behaviour, 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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