Royal Society Publishing

Molecular Biology and Genetics of Prion Diseases

Stanley B. Prusiner

Abstract

Scrapie was thought for many years to be caused by a virus. Enriching fractions from Syrian hamster (SHa) brain for scrapie infectivity led to the discovery of the prion protein (PrP). To date, no scrapie-specific nucleic acid has been found. As well as scrapie, prion diseases include bovine spongiform encephalopathy (BSE) 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. The prion inoculum was found to dictate which prions are synthesized de novo, even though the cells express both PrP genes. Discovery of mutations in the PrP genes of humans with GSS and familial CJD established that prion diseases 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(MoPrP-P101L) mice produced neurodegeneration in many of the recipient animals after prolonged incubation times. These and other results suggest that prions are devoid of foreign nucleic acid and are thus different from viruses and viroids. Studies on the structure of PrP<latex>$^{\text{Sc}}$</latex> and PrP<latex>$^{\text{C}}$</latex> suggest that the difference is conformational. Whether one or more putative <latex>$\alpha $</latex>-helices in PrP<latex>$^{\text{C}}$</latex> are converted into <latex>$\beta $</latex>-sheets during synthesis of PrP<latex>$^{\text{Sc}}$</latex> is unknown. Distinct prion isolates or `strains' exhibit different patterns of PrP<latex>$^{\text{Sc}}$</latex> accumulation which are independent of incubation times. Whether variations in PrP<latex>$^{\text{Sc}}$</latex> conformation are responsible for prion diversity remains to be established. Prion studies have given new insights into the etiologies of infectious, sporadic and inherited degenerative diseases.

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