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

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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.

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