GENETIC AND INFECTIOUS PRION DISEASES

Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). Prion diseases include scrapie of sheep and bovine spongiform encephalopathy of cattle as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker syndrome (GSS) of humans. Transgenic (Tg) mice expressing both SHa and mouse (Mo) PrP genes were used to probe the molecular basis of the species barrier and the mechanism of scrapie prion replication. Bioassays of brain extracts from two scrapie-infected Tg lines showed that the prion inoculum determines that prions are synthesized de novo, even though the cells express both PrP genes. Studies with artificial prions produced from chimeric Mo/SHaPrP transgenes underscore the concept that inoculated prion dictates which prion will be replicated. Discovery of mutations in the PrP genes of humans with GSS and familial CJD established that prion diseases are both genetic and infectious. Transgenic mice expressing high levels of MoPrP-P101L, corresponding to the GSS point mutation (P102L) in human PrP, spontaneously develop neurologic dysfunction, spongiform degeneration, and astrocytic gliosis. Inoculation of brain extracts prepared from these Tg (MoPrP-P101L) mice produced neurodegeneration in recipient animals after prolonged incubation times. These results are in accord with those of other studies and argue that prions are devoid of foreign nucleic acid. Structural investigations of cellular prion protein (PrP(C)) and prion protein scrapie (PrP(Sc)) suggest that the difference may be conformational. Conditions that diminished the beta-sheet content of PrP(Sc) were the same as those identified previously that inactivate prion infectivity. Whether prion diversity as reflected by distinct ''strains'' producing different patterns of PrP(Sc) accumulation is due to different conformers of PrP(Sc) remains to be established. Advances in the purification and characterization of both PrP(C) and PrP(Sc) seem to have identified the central event in PrP(Sc) synthesis and prion propagation, ie, the unfolding of PrP(C) followed by its refolding into PrP(Sc). These findings underscore the fundamental features of prion structure and propagation that differentiate prions from other transmissible pathogens.