THE USE OF TRANSGENIC MICE IN THE INVESTIGATION OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

The prion, the transmissible agent that causes spongiform encephalopat hies such as scrapie, bovine spongiform encephalopathy and Creutzfeldt -Jakob disease, is believed to be devoid of nucleic acid and to be ide ntical to PrPSc (prion protein: scrapie form), a modified form of the normal host protein PrPC (prion protein: cellular form) which is encod ed by the;single copy gene Pmp. The 'protein only' hypothesis proposes that PrPSc, when introduced into a normal host, causes the conversion of PrPC into PrPSc; it therefore predicts that an animal devoid of Pr PC should he resistant to prion diseases. The authors, generated homoz ygous Prnp(o/o) ('PrP knockout') mice and showed that, after inoculati on with prions, these mice remained free from scrapie for at least two years while wild-type controls all died within six months. There was no propagation of prions in the Prnp(o/o) animals. Surprisingly, heter ozygous Prnp(o/+) mice, which express PrPC at about half the normal le vel, also showed enhanced resistance to scrapie despite high levels of infectious agent and PrPSc in the brain at an early stage. After intr oduction of murine PrP transgenes, Prnp(o/o) mice became highly suscep tible to mouse - but not to hamster - prions, while the insertion of S yrian hamster PrP transgenes rendered the mice susceptible to hamster prions but much less susceptible to mouse prions. These complementatio n experiments enabled the application of reverse genetics. The authors prepared animals transgenic for genes encoding PrP with amino termina l deletions of various lengths and found that PrP that lacks 48 amino proximal amino acids (which comprise four of the five octa repeats of PrP) is still biologically active.