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Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice
Author(s) -
Li Aimin,
Piccardo Pedro,
Barmada Sami J,
Ghetti Bernardino,
Harris David A
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601726
Subject(s) - biology , neuroprotection , genetically modified mouse , transgene , virology , prion protein , microbiology and biotechnology , pharmacology , genetics , medicine , gene , disease
Familial prion diseases are due to dominantly inherited, germline mutations in the PRNP gene that encodes the prion protein (PrP). The cellular mechanism underlying the pathogenic effect of these mutations remains uncertain. To investigate whether pathogenic mutations impair a normal, physiological activity of PrP, we have crossed Tg(PG14) mice, which express PrP with an octapeptide insertion associated with an inherited prion dementia, with Tg(PrPΔ32–134) mice. Tg(PrPΔ32–134) mice, which express an N‐terminally truncated form of PrP, spontaneously develop a neurodegenerative phenotype that is stoichiometrically reversed by coexpression of wild‐type PrP. We find that, at equivalent expression levels, PG14 PrP is significantly less efficient than wild‐type PrP in suppressing the development of clinical symptoms and neuropathology in Tg(PrPΔ32–134) mice. Thus, our results suggest that some features of the neurological illness associated with inherited PrP mutations may be attributable to a loss of PrP neuroprotective function. This mechanism stands in contrast to the toxic gain‐of‐function mechanisms that are usually invoked to explain the pathogenesis of dominantly inherited neurodegenerative disorders.