Prion encephalopathies of animals and humans

S B Prusiner
Developments in Biological Standardization 1993, 80: 31-44
Studies over the past decade of the infectious prions causing scrapie and other transmissible neurodegenerative diseases support the hypothesis that these pathogens are novel. After convincing evidence was obtained showing that scrapie infectivity depends upon a protein component, the term "prion" was introduced to distinguish these infectious pathogens from others, including viroids and viruses. Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). 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 dictates which prions are synthesized de novo, even though the cells express both PrP genes. Discovery of mutations in the PrP gene from humans with Gerstmann-Sträussler-Scheinker disease (GSS), familial Creutzfeldt-Jakob disease and fatal familial insomnia established that prion diseases are unique among human illnesses--they are both genetic and infectious. Tg mice expressing MoPrP with the GSS point mutation spontaneously develop neurologic dysfunction, spongiform degeneration and astrocytic gliosis. Inoculation of brain extracts prepared from these Tg(GSSMoPrP) mice into Syrian hamsters and Tg mice expressing wild-type PrP transgenes has produced neurodegeneration in recipient animals after prolonged incubation times. If convincing data on serial passage of prions from the inoculated recipients can be obtained, then these results will argue that prions are devoid of foreign nucleic acid in accord with many other lines of evidence. Although it seems likely that transmissible prions are composed only of PrPSc molecules, a hypothetical second component such as a small polynucleotide remains a formal possibility. The conversion of PrPc into PrPSc is a post-translational process that probably occurs in the endocytic pathway. Studies on the structure of PrPSc and PrPC have been unsuccessful in defining a post-translational chemical modification that distinguishes one PrP isoform from the other. These findings suggest that the difference between PrPSc and PrPc may be conformational. The existence of distinct prion isolates or "strains" with different properties poses a conundrum. Distinct isolates produce the accumulation of PrPSc in particular sets of CNS neurons. Whether different conformers of or Asn-linked CHOs attached to PrPSc are produced in specific neurons and are responsible for the properties of distinct prion isolates is unknown. The study of prion diseases seems to be emerging as a new area of investigation at the interface of such disciplines as genetics, cell biology and virology.


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