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Cellular pathogenesis of prion diseases

Objective

Brief description:
Prion diseases (transmissible spongiform encephalopathies, TSE) are a group of rare fatal progressive neurological disorders including Creutzfeldt-Jakob disease (CJD) in humans as well as bovine spongiform encephalopathy (BSE) and scrapie in animals. Classical CJD has a world-wide incidence of one case per million per year. These diseases are unique in being both horizontally transmissible as well as sometimes hereditary diseases. The infectious agent has been termed prion. The only molecule consistently found in infectious preparations is the scrapie isoform of the prion protein (PrPsc). This protein derives from a normal cellular isoform of the prion protein (PrPC) which is encoded in the genome of all mammals investigated to date. As a prerequisite for the development of thereapeutic strategies a much better understanding of the spread of the infectious agent and its deleterious effects in infected individuals, i.e. the pathogenesis of prion diseases, is mandatory. Our collaboration addresses several crucial questions in the pathogenesis of prion diseases. It is focused on four aspects, in particular concerning the role of peripheral and central immune cells, the Iymphoreticular system and microglia:
The role of follicular dendritic cells and the Iymphoreticular system(LRS) in agent replication.
The involvement of the LRS particularly after oral infection.
Mechanisms of neuroinvasion after oral infection.
The activation or microglia and interaction of microglia with neurons leading to nerve cell death.
In this collaboration a number of highly complicated methodologies such as transgenic animal techniques, brain cell transplantation and microglial tissue culture will be joined to elucidate questions of cellular pathogenesis and spread of the infectious agent in the infected organism.

Keywords:
Prion diseases, transmissible spongiform encephalopathies, BSE, scrapie, Creutzfeldt-Jakob disease, lymphoreticular system, follicular dendritic cells, microglia, transgenic animals, cell culture

Prion diseases (transmissible spongiform encephalopathies, TSE) are a group of rare fatal progressive neurological disorders including Creutzfeldt-Jakob disease (CJD), Gerstmann-Str›ussler-Scheinker syndrome, fatal familial insomnia and kuru in humans as well as bovine spongi form encephalopathy (BSE) and scraple in animals. Classical CJD has a world-wide incidence of one case per million per year. These diseases are unique in being both horizontally transmissible as well as sometimes hereditary diseases (Prusiner, 1993). The infectious agent has been termed prion (Prusiner, 1982). This term here is used operationally independent of the exact biochemical nature of the agent. The only molecule consistently found in infectious preparations is the scrapie isoform of the prion protein (PrPsc). This protein derives from a normal cellular isoform of the prion protein (PrPC), which is encoded in the genome of all mammals investigated to date (Prusiner, 1991). PrPc is a glycoprotein of unknown function normally found in neurones (Kretzschmar et al. 1986) and glia (Moser et al. 1995). BSE has become a European scale problem.

The discovery of a new variant of CJD which most likely is caused by transmission of BSE to humans in 16 patients in the UK and France is cause for major concern. The number of people in the European Union possibly in the incubation period of the disease cannot at present be estimated. However, it is high time to devise new therapeutic strategies. As a prerequisite for this a much better understanding of the spread of the infectious agent and its deleterious effects in infected individuals, i.e. the pathogenesis of prion diseases, are mandatory. The projects presented here address several crucial questions in the pathogenesis of prion diseases.

Among these are:
1. The role of follicular dendritic cells and the lymphoreticular system(LRS) in agent replication;
2. The involvement of the LRS particularly after oral infection;
3. Mechanisms of neuroinvasion after oral infection;
4. The activation or microglia and interaction of microglia with neurons leading to nerve cell death. Thus several cellular mechanisms and interactions from peripheral infection to nerve cell damage are covered by the four partners in this application. This collaboration is focused on the cellular pathogenesis of prion diseases, in particular concerning the role of peripheral and central immune cells, the lymphoreticular system and microglia in an attempt to lay the foundation for future therapeutic strategies and does not touch on questions concerning the biochemical nature of the infectious agent which is being worked on by a great number of groups worldwide.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

LUDWIG-MAXIMILIANS UNIVERSITY OF MUNICH
Address
Marchioninistr. 17
81377 Muenchen
Germany

Participants (2)

COMMISSARIAT A L'ENERGIE ATOMIQUE
France
Address
60-68,Route Du Panorama 18
92265 Fontenay Aux Roses
UNIVERSITY OF ZURICH
Switzerland
Address
71,Raemistrasse 71
CH-8091 Zurich