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Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrP^Sc) binds to the cellular form (PrP^C), generating additional molecules of PrP^Sc. While several regions of the PrP^C molecule have been suggested to play a role in PrP^Sc 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 PrP^Sc. These results, in combination with biochemical data, demonstrate that residues 23–31 represent a critical site on PrP^C that binds to PrP^Sc 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 β-sheet-rich …