Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125

Aimin Li, Heather M. Christensen, Leanne R. Stewart, Kevin A. Roth, Roberto Chiesa, David A. Harris

Research output: Contribution to journalArticlepeer-review

Abstract

To identify sequence domains important for the neurotoxic and neuroprotective activities of the prion protein (PrP), we have engineered transgenic mice that express a form of murine PrP deleted for a conserved block of 21 amino acids (residues 105-125) in the unstructured, N-terminal tail of the protein. These mice spontaneously developed a severe neurodegenerative illness that was lethal within 1 week of birth in the absence of endogenous PrP. This phenotype was reversed in a dose-dependent fashion by coexpression of wild-type PrP, with five-fold overexpression delaying death beyond 1 year. The phenotype of Tg(PrPΔ105-125) mice is reminiscent of, but much more severe than, those described in mice that express PrP harboring larger deletions of the N-terminus, and in mice that ectopically express Doppel, a PrP paralog, in the CNS. The dramatically increased toxicity of PrPΔ105-125 is most consistent with a model in which this protein has greatly enhanced affinity for a hypothetical receptor that serves to transduce the toxic signal. We speculate that altered binding interactions involving the 105-125 region of PrP may also play a role in generating neurotoxic signals during prion infection.

Original languageEnglish
Pages (from-to)548-558
Number of pages11
JournalEMBO Journal
Volume26
Issue number2
DOIs
Publication statusPublished - Jan 24 2007

Keywords

  • Lethal
  • Neurodegeneration
  • Prion
  • Transgenic

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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