PRION PROTEIN TRANSGENES AND THE NEUROPATHOLOGY IN PRION-DISEASES

The concept that prions are novel pathogens which are different from b oth viroids and viruses has received increasing support from many aven ues of investigation over the past decade. Enriching fractions from Sy rian hamster (SHa) brain for scrapie prion infectivity led to the disc overy of the prion protein (PrP). Prion diseases of animals include sc rapie and ''mad cow'' disease; those of humans present as inherited, s poradic and infectious neurodegenerative disorders, two of which are c alled Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheink er disease (GSS). The inherited human prion diseases are genetically l inked to mutations in the PrP gene that result in non-conservative ami no acid substitutions. Transgenic (Tg) mice expressing PrP carrying a GSS mutation developed neurodegeneration spontaneously and produced pr ions de novo. In other studies, Tg mice expressing both SHa and mouse (Mo) PrP genes were used to demonstrate that the ''species barrier'' f or scrapie prions resides in the primary structure of PrP. This concep t was strengthened by the results of studies in which mice expressing chimeric Mo/human (Hu) PrP transgenes were constructed which differ fr om MoPrP by nine amino acids between residues 96 and 167. All of the T g(MHu2M) mice developed neurologic disease similar to 200 days after i noculation with brain homogenate from three patients who died of CJD. About 10% of TS(HuPrP) mice expressing HuPrP and non-Tg mice developed neurologic disease >500 days after inoculation with CJD prions. The d ifferent susceptibilities of Tg(HuPrP) and Tg(MHu2M) mice to human pri ons indicate that additional species specific factors such as chaperon e proteins are involved in prion replication. Diagnosis, prevention an d treatment of human prion diseases should be facilitated by study of Tg(MHu2M) mice. Our findings and those from other studies suggest that mutant and wtPrP interact, perhaps through a chaperone-like protein, during the pathogenesis of the prion diseases.