Molecular distinction between pathogenic and infectious properties of the prion protein

Roberto Chiesa, Pedro Piccardo, Elena Quaglio, Bettina Drisaldi, San Ling Si-Hoe, Masaki Takao, Bernardino Ghetti, David A. Harris

Research output: Contribution to journalArticle

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Abstract

Tg(PG14) mice express a prion protein (PrP) with a nine-octapeptide insertion associated with a human familial prion disease. These animals spontaneously develop a fatal neurodegenerative disorder characterized by ataxia, neuronal apoptosis, and accumulation in the brain of an aggregated and weakly protease-resistant form of mutant PrP (designated PG14spon). Brain homogenates from Tg(PG14) mice fail to transmit disease after intracerebral inoculation into recipient mice, indicating that PG14spon, although pathogenic, is distinct from PrPSc, the infectious form of PrP. In contrast, inoculation of Tg(PG14) mice with exogenous prions of the RML strain induces accumulation of PG14RML, a PrPSc form of the mutant protein that is infectious and highly protease resistant. Like PrPSc, both PG14spon and PG14RML display conformationally masked epitopes in the central and octapeptide repeat regions. However, these two forms differ profoundly in their oligomeric states, with PG14RML aggregates being much larger and more resistant to dissociation. Our analysis provides new molecular insight into an emerging puzzle in prion biology, the discrepancy between the infectious and neurotoxic properties of PrP.

Original languageEnglish
Pages (from-to)7611-7622
Number of pages12
JournalJournal of Virology
Volume77
Issue number13
DOIs
StatePublished - Jul 2003

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prions
PrPSc proteins
Prions
Mutant Proteins
Peptide Hydrolases
mice
Prion Diseases
Brain
proteinases
Ataxia
Neurodegenerative Diseases
brain
Epitopes
mutants
prion diseases
neurodegenerative diseases
protein aggregates
Apoptosis
epitopes
Prion Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Chiesa, R., Piccardo, P., Quaglio, E., Drisaldi, B., Si-Hoe, S. L., Takao, M., ... Harris, D. A. (2003). Molecular distinction between pathogenic and infectious properties of the prion protein. Journal of Virology, 77(13), 7611-7622. https://doi.org/10.1128/JVI.77.13.7611-7622.2003

Molecular distinction between pathogenic and infectious properties of the prion protein. / Chiesa, Roberto; Piccardo, Pedro; Quaglio, Elena; Drisaldi, Bettina; Si-Hoe, San Ling; Takao, Masaki; Ghetti, Bernardino; Harris, David A.

In: Journal of Virology, Vol. 77, No. 13, 07.2003, p. 7611-7622.

Research output: Contribution to journalArticle

Chiesa, R, Piccardo, P, Quaglio, E, Drisaldi, B, Si-Hoe, SL, Takao, M, Ghetti, B & Harris, DA 2003, 'Molecular distinction between pathogenic and infectious properties of the prion protein', Journal of Virology, vol. 77, no. 13, pp. 7611-7622. https://doi.org/10.1128/JVI.77.13.7611-7622.2003
Chiesa, Roberto ; Piccardo, Pedro ; Quaglio, Elena ; Drisaldi, Bettina ; Si-Hoe, San Ling ; Takao, Masaki ; Ghetti, Bernardino ; Harris, David A. / Molecular distinction between pathogenic and infectious properties of the prion protein. In: Journal of Virology. 2003 ; Vol. 77, No. 13. pp. 7611-7622.
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