Molecular Biology of Prion Diseases

Abstract

The transmissible agent that causes spongiform encephalopathies such as scrapie, the prion, is believed to be devoid of nucleic acid and identical with PrP^Sc, a modified form of PrP^c. PrP^c is a normal host protein encoded by a single copy gene (Prn-p) and is found predominantly on the surface of neurons. PrP^Sc, in contrast to PrP^c, is resistant to protease and accumulates intracellularly. Prusiner proposed that PrP^Sc, when introduced into a nominal host, causes the conversion of PrP^c or its precursor into PrP^Sc (”protein only” hypothesis). We generated homozygous Prn-p^ο/ο(“PrP knockout”) mice devoid of PrP^c. Prn-p^ο/ο mice inoculated with mouse scrapie prions remained free of scrapie symptoms for at least 2 years while wild-type controls all died within 6 months. There was no propagation of prions in the Prn-p^ο/ο animals. Introduction of murine PrP transgenes rendered Prn-p^ο/ο mice highly susceptible to mouse but not to hamster prions, while the introduction of Syrian hamster PrP transgenes rendered them susceptible to hamster but to a much lesser extent to mouse prions. Our experiments show that PrP^c, possibly at close to normal levels, is required for the usual susceptibility to scrapie and that lack of homology between incoming prions and the host’s PrP genes decreases susceptibility to disease. They also suggest that cattle or sheep devoid of the PrP gene might be viable and resistant to scrapie.