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 language | English |
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Pages (from-to) | 548-558 |
Number of pages | 11 |
Journal | EMBO Journal |
Volume | 26 |
Issue number | 2 |
DOIs | |
Publication status | Published - Jan 24 2007 |
Keywords
- Lethal
- Neurodegeneration
- Prion
- Transgenic
ASJC Scopus subject areas
- Genetics
- Cell Biology