Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers

The PrP gene of the host exerts a major influence over the outcome of trans missible spongiform encephalopathy (TSE) disease, but the mechanism by whic h this is achieved is not understood. We have introduced a specific mutatio n into the endogenous murine PrP gene using gene targeting to produce trans genic mice with a single amino acid alteration (proline to leucine) at amin o acid position 101 in their PrP protein (P101L). The effect of this altera tion on incubation time, targeting and PrPSc formation has been studied in TSE-infected animals. Transgenic mice carrying the P101L mutation in PrP ha ve remarkable differences in incubation time and targeting of central nervo us system pathology compared with wild-type littermates, following inoculat ion with infectivity from human, hamster, sheep and murine sources. This si ngle mutation can alter incubation time across three species barriers in a strain-dependent manner. These findings suggest a critical role for the str ucturally 'flexible' region of PrP in agent replication and targeting of TS E pathology.