Award details

Membrane trafficking and expression of prion protein: their role in TSE

Reference	BS308137
Principal Investigator / Supervisor	Professor Roger James Morris
Co-Investigators / Co-Supervisors	Professor Jean Manson, Mrs Patricia McBride
Institution	King's College London
Department	Experimental Pathology
Funding type	Research
Value (£)	292,715
Status	Completed
Type	Research Grant
Start date	01/12/1997
End date	30/06/2001
Duration	43 months

Abstract

The conversion of prion protein from its cellular (PrPc) to scrapie (PrPsc) form is both diagnostic of TSE infection and central to pathogenesis. We will identify the cellular basis of this conversion and its propagation from sites of infection to target neurons in the CNS. The endosomal trafficking of PrPc appears to be central to its pathogenic conversion. We will investigate, in cultures of polarised neurons, the cycling of PrPc between the cell surface and endosomes, and study the acute and chronic effects of scrapie infection upon this. Definitive proof of the role of endocytic trafficking upon the ability of PrPc to support TSE infection will be sought in cultured cells and in transgenic mice expressing hybrid proteins in which the membrane microenvironment and endocytic behaviour of PrP have been altered. To understand how expression of PrPc in vivo influences routes of infection and selective neurotoxicity, more effective immunohistochemistry is needed. We demonstrate an improved method that displays the cellular and subcellular distribution of PrPc, and its degradative processing; this will be used to study PrPc expression along routes of transmission to CNS target neurons. The increased sensitivity of this method may also enable the in vivo cellular response to infection to be studied at much earlier stages than has been possible. These approaches will substantially define the involvement of PrPc in TSE infection, and provide a rational basis for pharmacological intervention.

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	Biology of Spongiform Encephalopathies - Phase 3 (BS3) [1996-1997]
Funding Scheme	X – not Funded via a specific Funding Scheme

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