Genetics of Prion Diversity and Host Susceptibility

Abstract

Although all priori diseases, including familial Creutzfeldt-Jakob disease (CJD) and Gerstmann—Sträussler syndrome (GSS), are transmissible by inoculation, several features distinguish them from conventional infectious diseases. Scrapie, CJD and GSS are afebrile and proceed in the apparent absence of an immune response against the agent. The scrapie agent was long known to be highly resistant to procedures that destroy or modify nucleic acids, while being susceptible to procedures that hydrolyse, modify or denature proteins. A fresh perspective on scrapie and related disorders was provided by Prusiner (1982), who hypothesized that the scrapie agent was fundamentally different from other infectious particles and coined the term prion to distinguish the agent from viruses and viroids. Using biochemical procedures, including limited proteolysis, to enrich scrapie-infected hamster brain fraction for infectivity, a single protein with apparent molecular weight of 27000–30000 was discovered and designated PrP 27–30 (Bolton et al. 1982). Reverse genetics was used to clone the structural gene encoding PrP 27–30 (Oesch et al. 1985); the gene was found to be chromosomal, rather than agent-encoded, and is present in all mammals that have been tested (Basler et al. 1986; Westaway et al. 1989). PrP mRNA is expressed at similar levels in the brains of infected and uninfected animals, but scrapie-infected individuals have two isoforms of PrP compared with the single isoform in noninfected animals (Oesch et al. 1985).

This work was supported by grants NS22785 and NS14609 (S.B. Prusiner, program director) from the National Institutes of Health