Role of the PrP gene in transmissible spongiform encephalopathies

The transmissible agent that causes spongiform encephalopathies such as scrapie, the prion, is believed to be devoid of nucleic acid and identical with PrPSc, a modified form of PrPC. PrPC is a normal host protein encoded by a single copy gene (Prn-p) and is found predominantly on the surface of neurons. PrPSc, in contrast to PrPC, is resistant to protease and accumulates intracellularly. Prusiner proposed that PrPSc, when introduced into a normal host, causes the conversion of PrPC or its precursor into PrPSc ('protein only' hypothesis). If indeed PrP is an essential component of the prion, then an animal devoid of the PrP protein should be resistant to scrapie. We generated homozygous PrP 'knockout' mice. These Prn-p0/0 mice showed no gross abnormalities, and microscopic examination of brain sections of normal and Prn-p0/0 mice revealed no differences. Prn-p0/0, Prn-p+/+ and Prn-p0/+ mice were inoculated with scrapie agent; the clinical response as well as the prion titer at different time points are being determined.