The N-Terminal, Polybasic Region of PrPC Dictates the Efficiency of Prion Propagation by Binding to PrPSc

Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrPSc) binds to the cellular form (PrPC), generating additional molecules of PrPSc. While several regions of the PrPC molecule have been suggested to play a role in PrPSc formation based on in vitro studies, the contribution of these regions in vivo is unclear. Here, we report that mice expressing PrP deleted for a short, polybasic region at the N terminus (residues 23-31) display a dramatically reduced susceptibility to prion infection and accumulate greatly reduced levels of PrPSc. These results, in combination with biochemical data, demonstrate that residues 23-31 represent a critical site on PrPC that binds to PrPSc and is essential for efficient prion propagation. It may be possible to specifically target this region for treatment of prion diseases as well as other neurodegenerative disorders due to beta-sheet-rich oligomers that bind to PrPC.