title: Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125.
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(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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.forename: Heather M
authors.initials: HM
authors.lastname: Christensen
authors.forename: Leanne R
authors.initials: LR
authors.lastname: Stewart
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017353:Gene Deletion; D005804:Genes, Lethal; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008954:Models, Biological; D018621:PrPC Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018621:PrPC Proteins