NR AORK
AU Collinge,J.
TI Prion propagation, strains and interspecies transmission
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-05
PT Konferenz-Vortrag
AB Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein (PrPc). The central molecular event in prion replication is thought to be the conversion of PrPc into a self-propagating conformational isomer that accumulates as aggregated material (PrPsc). The existence of multiple prion strains has been difficult to explain in terms of a protein-only infectious agent but recent studies suggest that strain-specific phenotypes can be encoded by differences in PrP conformation and glycosylation. The ability of a protein to encode phenotypic information has important biological implications. The appearance of variant CJD (vCJD), and the clear experimental evidence that it is caused by exposure to BSE, highlighted the need to understand the molecular basis of prion propagation and the barriers limiting intermammalian transmission. It is probable that a significant fraction of the UK population, and to a lesser degree other populations, have been exposed to BSE prions. Interspecies transmission is limited by a transmission barrier, thought initially to be explained by the degree of primary structure homology between the prion proteins of inoculum and host, but in which prion strain type is clearly crucial. Both PrP amino acid sequence and strain type affect the 3D-structure of glycosylated PrP which will presumably, in turn, affect the efficiency of the protein protein interactions thought to determine prion propagation. Contribution of other components to the species barrier is probable and may involve interacting co-factors that mediate the efficiency of prion propagation: quantitative trait locus mapping studies are being applied in mouse to identify relevant genetic loci. The recognition of efficient sub-clinical infection of mice inoculated with Sc237 hamster prions, to which a near complete species barrier was thought to exist, fundamentally questions current definitions of species barriers, hitherto quantified on the basis of recognition of clinical disease in inoculated animals. In a long-term experimental programme, we have been exploring and characterising human prion strains and modelling human susceptibility to BSE prion infection, using a panel of transgenic mice expressing only human PrP with either M or V at polymorphic residue 129 and with other naturally occurring or experimental mutations and polymorphisms. Transgenic mice expressing human PrP M129, in common with mice expressing human PrP V129, lack a transmission barrier to disease when infected with classical CJD prions. However, mice expressing human PrP M129, but not V129, develop a high level of sub-clinical infection on challenge with vCJD or BSE prions. These mice, when inoculated with BSE prions, may develop the either the neuropathological and molecular phenotype of vCJD or a distinct phenotype that is indistinguishable from that of sporadic CJD with PrPsc type 2, suggesting that more than one BSE-derived prion strain might infect humans. The role of the residue 129 polymorphism in determining human susceptibility to prion infection and its role in prion strain selection and propagation has been further explored in parallel with structural studies of the effect of this polymorphism on PrP conformation. These and other studies on the molecular basis of prion strain diversity and interspecies transmission barriers will be reviewed.
AD John Collinge, MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, UK
SP englisch
PO Deutschland