The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region

Conformational conversion of the cellular isoform of prion protein, designated PrP, into the abnormally folded, amyloidogenic isoform, PrPSc, is an essential pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Lines of evidence indicate that the N-terminal domain, which includes the N-terminal, positively charged polybasic region and the octapeptide repeat (OR) region, is important for PrP to convert into PrPSc after infection with prions. To further gain insights into the role of the polybasic region and the OR region in prion pathogenesis, we generated two different transgenic mice, designated Tg(PrP3K3A)/Prnp(0/0) and Tg(PrP3K3A increment OR)/Prnp(0/0) mice, which express PrP with lysine residues at codons 23, 24, and 27 in the polybasic region mutated with or without a deletion of the OR region on the Prnp(0/0) background, respectively, and intracerebrally inoculated them with RML and 22L prions. We show that Tg(PrP3K3A)/Prnp(0/0) mice were highly resistant to the prions, indicating that lysine residues at 23, 24, and 27 could be important for the polybasic region to support prion infection. Tg(PrP3K3A increment OR)/Prnp(0/0) mice also had reduced susceptibility to RML and 22L prions equivalent to Tg(PrP3K3A)/Prnp(0/0) mice. The pre-OR region, including the polybasic region, of PrP3K3A increment OR, but not PrP3K3A, was unusually converted to a protease-resistant structure during conversion to PrP(Sc)3K3A increment OR. These results suggest that, while the OR region could affect the conformation of the polybasic region during conversion of PrP into PrPSc, the polybasic region could play a crucial role in prion pathogenesis independently of the OR region.