This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chiesa, R.
Right arrow Articles by Harris, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiesa, R.
Right arrow Articles by Harris, D. A.

 Previous Article  |  Next Article 

Journal of Virology, July 2003, p. 7611-7622, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7611-7622.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Molecular Distinction between Pathogenic and Infectious Properties of the Prion Protein

Roberto Chiesa,1,2 Pedro Piccardo,3 Elena Quaglio,1,{dagger} Bettina Drisaldi,1,{ddagger} San Ling Si-Hoe,1 Masaki Takao,3,§ Bernardino Ghetti,3 and David A. Harris1*

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110,1 Dulbecco Telethon Institute and Department of Neuroscience, Istituto di Ricerche Farmacologiche "Mario Negri," Milan 20157, Italy,2 Division of Neuropathology, Indiana University School of Medicine, Indianapolis, Indiana 462023

Received 8 January 2003/ Accepted 2 April 2003

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.

* Corresponding author. Mailing address: Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-4690. Fax: (314) 747-0940. E-mail: dharris{at}cellbio.wustl.edu.

{dagger} Present address: Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852.

{ddagger} Present address: Istituto di Ricerche Farmacologiche "Mario Negri," 20157 Milan, Italy.

§ Present address: Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, Canada.

Journal of Virology, July 2003, p. 7611-7622, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7611-7622.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chiesa, R., Piccardo, P., Biasini, E., Ghetti, B., Harris, D. A. (2008). Aggregated, Wild-Type Prion Protein Causes Neurological Dysfunction and Synaptic Abnormalities. J. Neurosci. 28: 13258-13267 [Abstract] [Full Text]  
  • Thackray, A. M., Hopkins, L., Spiropoulos, J., Bujdoso, R. (2008). Molecular and Transmission Characteristics of Primary-Passaged Ovine Scrapie Isolates in Conventional and Ovine PrP Transgenic Mice. J. Virol. 82: 11197-11207 [Abstract] [Full Text]  
  • Tank, E. M. H., Harris, D. A., Desai, A. A., True, H. L. (2007). Prion Protein Repeat Expansion Results in Increased Aggregation and Reveals Phenotypic Variability. Mol. Cell. Biol. 27: 5445-5455 [Abstract] [Full Text]  
  • Maas, E., Geissen, M., Groschup, M. H., Rost, R., Onodera, T., Schatzl, H., Vorberg, I. M. (2007). Scrapie Infection of Prion Protein-deficient Cell Line upon Ectopic Expression of Mutant Prion Proteins. J. Biol. Chem. 282: 18702-18710 [Abstract] [Full Text]  
  • Yin, S., Pham, N., Yu, S., Li, C., Wong, P., Chang, B., Kang, S.-C., Biasini, E., Tien, P., Harris, D. A., Sy, M.-S. (2007). Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans. Proc. Natl. Acad. Sci. USA 104: 7546-7551 [Abstract] [Full Text]  
  • Pietri, M., Caprini, A., Mouillet-Richard, S., Pradines, E., Ermonval, M., Grassi, J., Kellermann, O., Schneider, B. (2006). Overstimulation of PrPC Signaling Pathways by Prion Peptide 106-126 Causes Oxidative Injury of Bioaminergic Neuronal Cells. J. Biol. Chem. 281: 28470-28479 [Abstract] [Full Text]  
  • Yin, S., Yu, S., Li, C., Wong, P., Chang, B., Xiao, F., Kang, S.-C., Yan, H., Xiao, G., Grassi, J., Tien, P., Sy, M.-S. (2006). Prion Proteins with Insertion Mutations Have Altered N-terminal Conformation and Increased Ligand Binding Activity and Are More Susceptible to Oxidative Attack. J. Biol. Chem. 281: 10698-10705 [Abstract] [Full Text]  
  • Leliveld, S. R., Dame, R. T., Wuite, G. J. L., Stitz, L., Korth, C. (2006). The Expanded Octarepeat Domain Selectively Binds Prions and Disrupts Homomeric Prion Protein Interactions. J. Biol. Chem. 281: 3268-3275 [Abstract] [Full Text]  
  • Stewart, R. S., Harris, D. A. (2005). A Transmembrane Form of the Prion Protein Is Localized in the Golgi Apparatus of Neurons. J. Biol. Chem. 280: 15855-15864 [Abstract] [Full Text]  
  • Stewart, R. S., Piccardo, P., Ghetti, B., Harris, D. A. (2005). Neurodegenerative Illness in Transgenic Mice Expressing a Transmembrane Form of the Prion Protein. J. Neurosci. 25: 3469-3477 [Abstract] [Full Text]  
  • Fioriti, L., Dossena, S., Stewart, L. R., Stewart, R. S., Harris, D. A., Forloni, G., Chiesa, R. (2005). Cytosolic Prion Protein (PrP) Is Not Toxic in N2a Cells and Primary Neurons Expressing Pathogenic PrP Mutations. J. Biol. Chem. 280: 11320-11328 [Abstract] [Full Text]  
  • Chiesa, R., Piccardo, P., Dossena, S., Nowoslawski, L., Roth, K. A., Ghetti, B., Harris, D. A. (2005). Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease. Proc. Natl. Acad. Sci. USA 102: 238-243 [Abstract] [Full Text]  
  • Morante, S., Gonzalez-Iglesias, R., Potrich, C., Meneghini, C., Meyer-Klaucke, W., Menestrina, G., Gasset, M. (2004). Inter- and Intra-octarepeat Cu(II) Site Geometries in the Prion Protein: IMPLICATIONS IN Cu(II) BINDING COOPERATIVITY AND Cu(II)-MEDIATED ASSEMBLIES. J. Biol. Chem. 279: 11753-11759 [Abstract] [Full Text]  
  • Stewart, R. S., Harris, D. A. (2003). Mutational Analysis of Topological Determinants in Prion Protein (PrP) and Measurement of Transmembrane and Cytosolic PrP during Prion Infection. J. Biol. Chem. 278: 45960-45968 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»