A gene-targeted mouse model of P102L Gerstmann-Sträussler-Scheinker syndrome.

Transgenic mice that contain a proline to leucine mutation at amino acid 101 in the endogenous murine PrP gene have been produced by gene targeting. This line of mice was generated to model the mutation thought to be responsible for P102L GSS, a familial TSE disease in humans. Genetargeted 101LL mice showed no evidence of spontaneous TSE disease in their lifetime and were unable to transmit any neurologic disease to other 101LL transgenic mice. 101LL mice have, however, been shown to demonstrate altered susceptibility to several TSE strains, and have shown reduced incubation times with TSE agents that do not readily transmit to wild-type mice. The 101L mutation does not appear to destabilize PrP and promote conversion to PrPSc, because incubation times are increased with mouse-passaged TSE strains and vCJD. PrPSc also can be difficult to detect in 101LL mice infected with some TSE strains. We, therefore, have been unable to substantiate the existence of either genetic disease or infectious PrP with the P101L transgenic model, but have provided evidence of altered incubation times of TSE disease in mice carrying the 101L mutation in their PrP protein. We also have shown that mutations in the N-terminal region of PrP can have a major influence over both incubation time and targeting of TSE disease.