Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice.

The N-terminal polybasic region of the normal prion protein, PrP, which encompasses residues 23-31, is important for prion pathogenesis by affecting conversion of PrP into the pathogenic isoform, PrP. We previously reported transgenic mice expressing PrP with residues 25-50 deleted in the PrP-null background, designated as Tg(PrP∆preOR)/Prnp mice. Here, we produced two new lines of Tg(PrP∆preOR)/Prnp mice, each expressing the mutant protein, PrP∆preOR, 1.1 and 1.6 times more than PrP in wild-type mice, and subsequently intracerebrally inoculated RML and 22L prions into them. The lower expresser showed slightly reduced susceptibility to RML prions but not to 22L prions. The higher expresser exhibited enhanced susceptibility to both prions. No prion transmission barrier was created in Tg(PrP∆preOR)/Prnp mice against full-length PrP. PrP∆preOR accumulated in the brains of infected Tg(PrP∆preOR)/Prnp mice less than PrP in control wild-type mice, although lower in RML-infected Tg(PrP∆preOR)/Prnp mice than in 22L-infected mice. Prion infectivity in infected Tg(PrP∆preOR)/Prnp mice was also lower than that in wild-type mice. These results indicate that deletion of residues 25-50 only slightly affects prion susceptibility, the conversion of PrP into PrP, and prion infectivity in a strain-specific way. PrP∆preOR retains residues 23-24 and lacks residues 25-31 in the polybasic region. It is thus conceivable that residues 23-24 rather than 25-31 are important for the polybasic region to support prion pathogenesis. However, other investigators have reported that residues 27-31 not 23-24 are important to support prion pathogenesis. Taken together, the polybasic region might support prion pathogenesis through multiple sites including residues 23-24 and 27-31.