Species barrier in prion diseases: a kinetic interpretation based on the conformational adaptation of the prion protein.
Prion diseases are thought to result from the conformational change of the normal cellular prion protein to a pathogenic protease-resistant isoform. However, brain extracts not containing the protease-resistant isoform of the prion protein can be infectious following interspecies transmission. The 'protein-only' hypothesis of pathogenesis is extended to provide possible explanations which could be interpreted in terms of a different infectious agent. It is proposed that normal cellular protein (PrPC) may be transformed into a form (PrP*) that is conformationally distinct from the host-specific abnormal isoform (PrPSc). In infection from a heterologous donor, the dimeric forms of heterologous PrPSc, which may catalyse the formation of host PrP* from PrPC, host PrP* and host PrPSc are all considered to be capable of catalysing, to some extent, the conversion of PrPC into PrPSc. However, depending on the species involved, PrP* may, or may not, be pathogenic, and may, or may not, be sensitive to proteolysis. It is shown, by numerical integration of the differential rate equations derived from this model, that a strain may be stabilized after two or three passages through a different species and that transmission might occur in the absence of detectable protease-resistant prion protein. The natural transmission of scrapie to cattle is discussed in relation to the model.
Kellershohn
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N
Service d'Imagerie Cellulaire, URA D2227 CNRS, Bât. 440, Université Paris-Sud, Centre d'Orsay, 91405 Orsay Cedex, France.
Laurent
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M
D000818:Animals; D002417:Cattle; D019281:Dimerization; D010450:Endopeptidases / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism / Q000472:pathogenicity; D017096:Prion Diseases / Q000209:etiology / Q000378:metabolism* / Q000635:transmission*; D011328:Prions / Q000737:chemistry* / Q000378:metabolism / Q000472:pathogenicity*; D011487:Protein Conformation; D013045:Species Specificity; D013816:Thermodynamics
D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D010450:Endopeptidases