Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice

Aimin Li, Pedro Piccardo, Sami J. Barmada, Bernardino Ghetti, David A. Harris

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2777-2785
Number of pages9
JournalEMBO Journal
Volume26
Issue number11
DOIs
StatePublished - Jun 6 2007

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Transgenic Mice
Prions
Mutation
Prion Proteins
Prion Diseases
Germ-Line Mutation
Poisons
Neurodegenerative Diseases
Genes
Phenotype

Keywords

  • Mutation
  • Neuroprotection
  • Octapeptide
  • Prion
  • Transgenic

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice. / Li, Aimin; Piccardo, Pedro; Barmada, Sami J.; Ghetti, Bernardino; Harris, David A.

In: EMBO Journal, Vol. 26, No. 11, 06.06.2007, p. 2777-2785.

Research output: Contribution to journalArticle

Li, Aimin ; Piccardo, Pedro ; Barmada, Sami J. ; Ghetti, Bernardino ; Harris, David A. / Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice. In: EMBO Journal. 2007 ; Vol. 26, No. 11. pp. 2777-2785.
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