NR AVZV
AU Li,A.; Christensen,H.M.; Stewart,L.R.; Roth,K.A.; Chiesa,R.; Harris,D.A.
TI Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125
QU EMBO Journal 2007 Jan 24; 26(2): 548-58
PT journal article; research support, n.i.h., extramural; research support, non-u.s. gov't
AB 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.
MH Animals; Animals, Newborn; Brain/metabolism/pathology; Cells, Cultured; Gene Deletion; *Genes, Lethal; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Models, Biological; PrPc Proteins/*genetics/metabolism
AD Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA
SP englisch
PO England