NR AGHJ
AU Kellershohn,N.; Laurent,M.
TI Species barrier in prion diseases: a kinetic interpretation based on the conformational adaptation of the prion protein.
QU Biochemical Journal 1998 Sep 15; 334(3): 539-45
PT journal article
AB 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.
MH Animal; Cattle; Dimerization; Endopeptidases/pharmacology; Human; Kinetics; *Models, Biological; PrPc Proteins/chemistry/metabolism; PrPsc Proteins/chemistry/metabolism/pathogenicity; Prion Diseases/etiology/*metabolism/*transmission; Prions/*chemistry/metabolism/*pathogenicity; Protein Conformation; Species Specificity; Support, Non-U.S. Gov't; Thermodynamics
AD Service d'Imagerie Cellulaire, URA D2227 CNRS, Bat. 440, Universite Paris-Sud, Centre d'Orsay, 91405 Orsay Cedex, France.
SP englisch
PO England