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

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(PrPDelta105-125) 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 PrPDelta105-125 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.

Pubmed ID: 17245437


  • Li A
  • Christensen HM
  • Stewart LR
  • Roth KA
  • Chiesa R
  • Harris DA


The EMBO journal

Publication Data

January 24, 2007

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS040975
  • Agency: NINDS NIH HHS, Id: NS04691003
  • Agency: NINDS NIH HHS, Id: NS35107
  • Agency: Telethon, Id: TCR05006

Mesh Terms

  • Animals
  • Animals, Newborn
  • Brain
  • Cells, Cultured
  • Gene Deletion
  • Genes, Lethal
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Models, Biological
  • PrPC Proteins