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Mice, homozygous for prion protein (PrP) gene ablation (Prn-p°/°), develop normally and remain well >500 days after inoculation with murine scrapie prions. In contrast, wild-type mice developed scrapie <165 days after inoculation and most Prn-p°/+ mice, heterozygous for disrup-

Transgenic mice expressing chimeric prion protein (PrP) genes derived from Syrian hamster (SHa) and mouse (Mo) PrP genes were constructed. One SHa/MoPrP gene, designated MH2M PrP, contains five amino acid substitutions encoded by SHaPrP, while another construct, designated MHM2 PrP, has two substitutions. Transgenic (Tg) (MH2M PrP) mice were susceptible to both Syrian hamster and mouse prions, whereas three lines expressing MHM2 PrP were resistant to Syrian hamster prions. The brains of Tg(MH2M PrP) mice dying of scrapie contained chimeric PrPSc and prions with an artificial host range favoring propagation in mice that express the corresponding chimeric PrP and were also transmissible, at reduced efficiency, to nontransgenic mice and hamsters. Our findings provide genetic evidence for homophilic interactions between PrPSc in the inoculum and PrPc synthesized by the host.

Scrapie is characterized by the accumulation of a protease-resistant isform of the prion protein PrP&. Limited proteolysis and chaotropes were used to map the distribution of PrP& in cryostat sections of scrapie-infected brain blotted onto nitrocellulose membranes, de ted histoblots. Proteolysis was omitted in order to map the cellular isoform of the prion protein (PrPC)

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Studies with transgenic mice expressing foreign and mutant prion protein (PrP) genes have provided a wealth of new knowledge about the structure of the prion particle, the pathogenesis of prion diseases, and the events that feature in the replication of prions (Scott et al. 1989;Hsiao et al. 1990;Prusiner et al. 1990;Westaway et al. 1991). Investigations of transgenic (Syrian hamster PrP) [Tg(SHaPrP)] mice expressing SHaPrP demonstrated that PrP sc in the inoculum dictates whether mouse prions (Mo prions) or Syrian hamster prions (SHa prions) will be produced. Furthermore, the scrapie incubation times and neuropathology are determined by the particular prion synthesized. Although no physical evidence is available, it seems likely that PrP c and PrP sc transiently form a complex during the synthesis of nascent PrP sc molecules Prusiner 1991).Early studies of Dickinson and colleagues not only identified inbred strains of mice with short or long incubation times, but also distinct isolates of the scrapie agent distinguishable by their different incubation times and neuropathologic lesions Dickinson 1968, 1973; Dickinson and Meikle 4present address:

Different prion Isolates, often referred to as "strains," present an enigma because considerable evidence argues that prions are devoid of nucleic acid. To investigate prion diversity, we inoculated three "strains" of prions into congenic and transgenic mice harboring variable numbers of two dierent alleles, designated a and b, of the prion protein (rP) structural gene, Prn-p. The length of the incubation time was inversely related to the number of Pm-p genes in mice inoculated with the Rocky Mountain Laboratory (RML) prion strain. Results with mice lacking this locus (Prnpe/) and ransgenic mice argue that long incubation times are not a dominant trait as thought for many years, but rather they are due to reduced levels of the substrate PrPC-A (cellular isoform of PrP, allotype A) in (Prn-p5 x Pvn-pb)Fi mice. In contrast, the Prn-pa gene extended incubation times in mice inoculated with the 87V and 22A prion strains, whereas the Prm-pb gene was permissive. Experiments with the 87V Isolate suggest that a genetic locus distinct from Prn-p controls deposition of the scraple isoform of PrP (Prs) and attendant neuropathology.Each prion isolate produced di hable patterns of PrPsc accumulation in brain; of note, the patterns in Prn-pa and Prn-pb congenic mice inculated with RML prions were more different than those in congenic Prn-9b mice with RML or 22A prions. Our results suggest that scrapie "strain-specific" incubation times can be explained by differences in the relative efficiency of allotypic interactions that lead to conversion of PrPC Into prPsc.

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