Strain-specified relative conformational stability of the scrapie prion protein

Studies of prion biology and diseases have elucidated several new concepts, but none was more heretical than the proposal that the biological properti es that distinguish different prion strains are enciphered in the disease-c ausing prion protein (PrPSC). To explore this postulate, we examined the pr operties of PrPSC from eight prion isolates that propagate in Syrian hamste r (SHa). Using resistance to protease digestion as a marker for the undenat ured protein, we examined the conformational stabilities of these PrPSC mol ecules. All eight isolates showed sigmoidal patterns of transition from nat ive to denatured PrPSC as a function of increasing guanidine hydrochloride (GdnHCl) concentration. Half-maximal denaturation occurred at a mean value of 1.48 M GdnHCl for the Sc237, HY, SHa(Me7), and MT-CS isolates, all of wh ich have similar to 75-d incubation periods; a concentration of 1.08 M was found for the DY strain with a similar to 170-d incubation period and simil ar to1.25 M for the SHa(RML) and 139H isolates with similar to 180-d incuba tion periods. A mean value of 1.39 M GdnHCl for the Me7-H strain with a sim ilar to 320-d incubation period was found. Based on these results, the eigh t prion strains segregated into four distinct groups. Our results support t he unorthodox proposal that distinct PrPSC conformers encipher the biologic al properties of prion strains.