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

R M Barron, V Thomson, E Jamieson, D W Melton, J Ironside, R Will, J C Manson

Research output: Contribution to journalArticlepeer-review

Abstract

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 PrP(Sc) 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.
Original languageEnglish
Pages (from-to)5070-8
Number of pages9
JournalEMBO Journal
Volume20
Issue number18
DOIs
Publication statusPublished - 17 Sep 2001

Keywords

  • Amino Acid Sequence
  • Animals
  • Brain
  • Creutzfeldt-Jakob Syndrome
  • Cricetinae
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptide Fragments
  • Point Mutation
  • PrPSc Proteins
  • Prion Diseases
  • Prions
  • Recombinant Proteins
  • Scrapie
  • Sequence Homology, Amino Acid
  • Sheep
  • Species Specificity
  • Time Factors

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