期刊
EMBO JOURNAL
卷 26, 期 2, 页码 548-558出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601507
关键词
lethal; prion; neurodegeneration; transgenic
资金
- NINDS NIH HHS [NS04691003, NS040975, R01 NS040975, R01 NS035107, NS35107] Funding Source: Medline
- Telethon [TCR05006] Funding Source: Medline
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(PrP Delta 105-125) 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 PrP Delta 105-125 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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