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Validating hydroxylation of the prion protein in TSE diagnosis

Reference	BBS/E/I/00000933
Principal Investigator / Supervisor	Dr Andrew Gill
Co-Investigators / Co-Supervisors	Dr John McCauley
Institution	The Pirbright Institute
Department	The Pirbright Institute Department
Funding type	Research
Value (£)	2,942
Status	Completed
Type	Institute Project
Start date	01/10/2002
End date	30/09/2005
Duration	36 months

Abstract

An abnormal form of the prion protein, PrPSc, is deposited in the brain during pathogenesis of the transmissible spongiform encephalopathies (TSEs), where it is a useful marker for both disease and infectivity and thus for post-mortem diagnosis of TSEs. Several covalent post-translational modifications have been identified in both normal (PrPc) and abnormal (PrPSc) prion protein such as asparagine-linked glycosylation, disulphide bridge formation and phospho-inositol glycolipid membrane anchor addition. At IAH Compton, we have recently identified a novel pro-collagen-like post-translational modification in PrP - 4-hydroxylation of proline 44 in the N-terminal region of the molecule (Gill et al, 2000). We also detected HO-Pro44 peptides at low abundance in brain PrPSc. We believe this abnormal, hydroxylated protein may be a marker for infected vascular (and other) epithelial cells in the brain and peripheral tissues that normally produce pro-collagen modifying enzymes. The position of HO-Pro44 peptides within the protease-sensitive part of PrPSc make it likely this marker of peripheral infection will be shed into blood, urine and lymphoid drainage fluid. This putative catabolic release from otherwise inaccessible sites of formation makes this modified polypeptide an excellent target for a non-invasive diagnostic test. We have developed a mass spectrometric assay for HO=Pro44 peptides that can detect as little as 50 fmoles in a blood serum matrix and aim to further develop this methodology and to investigate the prevalence of 4-hydroxyproline PrP formation, in addition to other modifications, in a range of normal and diseased tissues and body fluids. These data will be used to develop a non-invasive diagnostic methods based around this molecular target.

Summary

unavailable

Committee	Closed Committee - Agri-food (AF)
Research Topics	X – not assigned to a current Research Topic
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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