SCRAPIE SUSCEPTIBILITY-LINKED POLYMORPHISMS MODULATE THE IN-VITRO CONVERSION OF SHEEP PRION PROTEIN TO PROTEASE-RESISTANT FORMS

Prion diseases are natural transmissible neurodegenerative disorders i n humans and animals. They are characterized by the accumulation of a protease-resistant scrapie-associated prion protein (PrPSc) of the hos t-encoded cellular prion protein (PrPC) mainly in the central nervous system. Polymorphisms in the PrP gene are linked to differences in sus ceptibility for prion diseases. The mechanisms underlying these effect s are still unknown. Here we describe studies of the influence of shee p PrP polymorphisms on the conversion of PrPC into protease-resistant forms. In a cell-free system, sheep Prp(Sc) induced the conversion of sheep PrPC into protease-resistant PrP (PrP res) similar or identical to PrPSc. Polymorphisms present in either PrPC or PrPSc had dramatic e ffects on the cell-free conversion efficiencies. The PrP variant assoc iated with a high susceptibility to scrapie and short survival times o f scrapie-affected sheep was efficiently converted into PrP-res. The w ild-type PrP variant associated with a neutral effect on susceptibilit y and intermediate survival times was converted with intermediate effi ciency. The PrP variant associated with scrapie resistance and long su rvival times was poorly converted. Thus the in vitro conversion charac teristics of the sheep PrP variants reflect their linkage with scrapie susceptibility and survival times of scrapie-affected sheep. The modu lating effect of the polymorphisms in PrPC and PrPSc on the cell-free conversion characteristics suggests that, besides the species barrier, polymorphism barriers play a significant role in the transmissibility of prion diseases.