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 PrPC, 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 PrPC 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)/Prnp0/0 and Tg(PrP3K3A∆OR)/Prnp0/0 mice, which express PrPC 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 Prnp0/0 background, respectively, and intracerebrally inoculated them with RML and 22L prions. We show that Tg(PrP3K3A)/Prnp0/0 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∆OR)/Prnp0/0 mice also had reduced susceptibility to RML and 22L prions equivalent to Tg(PrP3K3A)/Prnp0/0 mice. The pre-OR region, including the polybasic region, of PrP3K3A∆OR, but not PrP3K3A, was unusually converted to a protease-resistant structure during conversion to PrPSc3K3A∆OR. These results suggest that, while the OR region could affect the conformation of the polybasic region during conversion of PrPC into PrPSc, the polybasic region could play a crucial role in prion pathogenesis independently of the OR region.