Molecular biology of prions causing infectious and genetic encephalopathies of humans as well as scrapie of sheep and BSE of cattle

S B Prusiner
Developments in Biological Standardization 1991, 75: 55-74
Considerable progress has been made in deciphering the role of an abnormal isoform of the prion protein (PrP) in scrapie of animals and Gerstmann-Sträussler syndrome (GSS) of humans. Transgenic (Tg) mice expressing both Syrian hamster (Ha) and mouse (Mo) PrP genes, which encode proteins differing at 16 residues out of 254, were used to probe the mechanism of scrapie prion replication. Four Tg lines expressing HaPrP exhibited distinct incubation times ranging from 48 to 277 days after Ha prion inoculation, which were inversely correlated with the steady-state levels of HaPrP mRNA and HaPrPc. Bioassays of brain extracts from two scrapie-infected Tg lines showed that the prion inoculum dictates which prions are synthesized de novo, even though the cells express both PrP genes. Tg mice inoculated with Ha prions had approximately 10(9) ID50 units of Ha prions per gram of brain while less than 10 units of Mo prions were found. Conversely, Tg mice inoculated with Mo prions had approximately 10(6) ID50 units of Mo prions and less than 10 units of Ha prions. Consistent with the analysis of prion synthesis, Tg mice inoculated with Ha prions exhibited neuropathologic changes characteristic of hamsters with scrapie while Mo prions produced changes similar to those in non-Tg mice with scrapie. Our results argue that species specificity of scrapie prions resides in the primary structure of PrP and formation of infectious prions is initiated by a species-specific interaction between PrPSc in the inoculum and homologous, cellular PrP. Studies on Syrian, Armenian and Chinese hamsters suggest that the domain of the PrP molecule between codons 100 and 120 controls both the length of the incubation time and the deposition of PrP in amyloid plaques. Ataxic GSS in families shows genetic linkage to a mutation in the PrP gene leading to the substitution of Leu for Pro at codon 102. Discovery of a point mutation in the PrP gene from humans with GSS established that GSS is unique among human diseases--it is both genetic and infectious. These results have revised thinking about sporadic Creutzfeldt-Jakob disease (CJD) suggesting it may arise from a somatic mutation. Pulse-chase radiolabeling experiments of scrapie-infected cultures of mouse neuroblastoma cells indicate that protease-resistant PrPSc is synthesized during the chase period with t1/2 approximately 15 h from a protease-sensitive precursor, consistent with the conclusion that PrPc and PrPSc differ due to a post-translational event.(ABSTRACT TRUNCATED AT 400 WORDS)

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