TRANSMISSION OF CREUTZFELDT-JAKOB-DISEASE FROM HUMANS TO TRANSGENIC MICE EXPRESSING CHIMERIC HUMAN-MOUSE PRION PROTEIN

Transgenic (Tg) mice were constructed that express a chimeric prion pr otein (PrP) in which a segment of mouse (Mo) PrP was replaced with the corresponding human (Hu) PrP sequence. The chimeric PrP, designated M Hu2MPrP, differs from MoPrP by 9 amino acids between residues 96 and 1 67. All of the Tg(MHu2M) mice developed neurologic disease approximate to 200 days after inoculation with brain homogenates from three patie nts dying of Creutzfeldt-Jakob disease (CJD). Inoculation of Tg(MHu2M) mice with CJD prions produced MHu2MPrP(Sc) (where PrPSc is the scrapi e isoform of PrP); inoculation with Mo prions produced MoPrPSc. The pa tterns of MHu2MPrP(Sc) and MoPrPSc accumulation in the brains of Tg(MH u2M) mice were different. About 10% of Tg(HuPrP) mice expressing HuPrP and non-Tg mice developed neurologic disease >500 days after inoculat ion with CJD prions. The different susceptibilities of Tg(BuPrP) and T g(MHu2M) mice to Hu prions indicate that additional species-specific f actors are involved in prion replication. Diagnosis, prevention, and t reatment of Hu prion diseases should be facilitated by Tg(MHu2M) mice.