Award details

Validating hydroxylation of the prion protein in TSE diagnosis

ReferenceBBS/E/I/00000933
Principal Investigator / Supervisor Dr Andrew Gill
Co-Investigators /
Co-Supervisors
Dr John McCauley
Institution The Pirbright Institute
DepartmentThe Pirbright Institute Department
Funding typeResearch
Value (£) 2,942
StatusCompleted
TypeInstitute Project
Start date 01/10/2002
End date 30/09/2005
Duration36 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 TopicsX – not assigned to a current Research Topic
Research PriorityX – Research Priority information not available
Research Initiative X - not in an Initiative
Funding SchemeX – not Funded via a specific Funding Scheme
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