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  • The EMBO Journal (2001) 20, 5070 - 5078
  • doi:10.1093/emboj/20.18.5070

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

Rona M. Barron1, Val Thomson1, Elizabeth Jamieson1, David W. Melton2, James Ironside3, Robert Will3 and Jean C. Manson1

  1. Institute for Animal Health, Neuropathogenesis Unit, West Mains Road Edinburgh, UK
  2. Sir Alastair Currie CRC Laboratories, Molecular Medicine Centre, Western General Hospital Edinburgh, UK
  3. CJD Surveillance Unit, Western General Hospital, Edinburgh, UK

Correspondence to:

Jean C. Manson, E-mail: jean.manson@bbsrc.ac.uk

Received 15 January 2001; Accepted 27 July 2001; Revised 11 June 2001

The PrP gene of the host exerts a major influence over the outcome of transmissible spongiform encephalopathy (TSE) disease, but the mechanism by which this is achieved is not understood. We have introduced a specific mutation into the endogenous murine PrP gene using gene targeting to produce transgenic mice with a single amino acid alteration (proline to leucine) at amino acid position 101 in their PrP protein (P101L). The effect of this alteration on incubation time, targeting and PrPSc formation has been studied in TSE-infected animals. Transgenic mice carrying the P101L mutation in PrP have remarkable differences in incubation time and targeting of central nervous system pathology compared with wild-type littermates, following inoculation with infectivity from human, hamster, sheep and murine sources. This single mutation can alter incubation time across three species barriers in a strain-dependent manner. These findings suggest a critical role for the structurally 'flexible' region of PrP in agent replication and targeting of TSE pathology.

  • Keywords:

    • P101L PrP,
    • prion diseases,
    • species barrier,
    • transmissible spongiform encephalopathies,
    • vCJD