Skip to main content

Trafficking pathways of normal and pathologic isoforms of the prion protein

Objective




The appearance of Bovine Spongiform Encephalopathy (BSE) in Europe and its possible transmission to humans has put a priority on research on transmissible spongiform encephalopathies (TSE). TSE are long known fatal neurodegenerative disorders of humans and animals that are characterized by dementia, motor dysfunction, and cerebral amyloidosis. These disorders are unique because they can be either infectious, genetic or sporadic in origin. All three forms result from a posttranslational alteration in the conformation of a host-encoded membrane glycoprotein called PrPc, which stands for the cellular isoform of the prion protein. Conversion of this normal isoform from an a-helical, readily proteolysed surface protein, to the scrapie isoform of PrP, PrPSc, a highly protease resistant, B-pleated sheet-containing hydrophobic aggregate is not only diagnostic of TSE infection, but is widely taken to be the defining infectious event and source of the subsequent neuropathology. Little is know about PrP which has a central role in TSE as demonstrated by the absolute relationship between PrP expression and development or transmission of TSE. Defining the mechanisms underlying the generation of prpSc from PrPc has now become one of the central issues in understanding the pathogenesis of prion diseases.
It is our contention that the conversion of prion protein from PrPc, to the pathogenic PrPSc, is strongly influenced by, and almost certainly requires, the normal trafficking of prion protein on cells. This perspective has important implications, not only for understanding the basic mechanism of the disease, but also for developing prophylactic and therapeutic measures, and for diagnosis. Despite the intense research interest in TSE, the cellular basis for the pathogenic conversion of PrP is an area that is relatively neglected, and many basic facts need to be established.
We propose here a coordinated effort to examine the trafficking of the different isoforms of PrP, in a cohesive strategy to understand the function and the pathogenic conversion of the protein. This project uniquely combines highly complementary and multi-disciplinary generic technologies of individual members with well characterized experimental systems. These technologies and systems comprise computer modeling, in-vitro system, functional assays and cell culture models, all of which in combination will allow us to examine the trafficking of normal and pathologic forms of PrP from synthesis to degradation.
Importantly, this proposal brings five groups that have not
previously worked oz TSE together with two more experienced groups in the field. This is a unique opportunity to join forces and benefit, on one hand, from the expertise of groups working previously on Alzheimer's Disease, protein modeling, cellular trafficking or glycolipids, and on the other hand, of well trained groups working on TSE.
The general measurable objectives of this proposal are: i) defining the biosynthetic pathways and maturation of PrP, ii) understanding the molecular basis of the endocytosis and recycling of the protein on the cell surface, iii) analyzing the proteolitic cleavage of PrP and its importance in the function and the conversion of the protein, and iv) examining the degradation of PrP in normal cells, and in cells infected with TSE. Achievement of the assigned objectives will generate comprehensive information about the fate of PrP in the cell and will lead to new strategies for diagnosis, treatment and prevention of TSE.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
Address
Rue De La Cardonille 141
34396 Montpellier
France

Participants (6)

BIRKBECK COLLEGE
United Kingdom
Address
Malet Street
WC1E 7HX London
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
France
Address
Route Des Lucioles 660
06560 Valbonne
Institut Curie
France
Address
26,Rue D'ulm
75231 Paris
UNIVERSITA DEGLI STUDI DI NAPOLI FEDERICO II
Italy
Address
Via Sergio Pansini 5
80131 Napoli
UNIVERSITY COLLEGE CORK, NATIONAL UNIVERSITY OF IRELAND, CORK
Ireland
Address
Lee Maltings, Prospect Row
30 Cork
United Medical and Dental Schools of Guy's and St Thomas's Hospitals
United Kingdom
Address
London Bridge
SE1 9RT London