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Journal of Virology, March 2007, p. 2831-2837, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02157-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cytosolic Prion Protein Toxicity Is Independent of Cellular Prion Protein Expression and Prion Propagation{triangledown}

Eric M. Norstrom,1 Mark F. Ciaccio,1 Benjamin Rassbach,1 Robert Wollmann,2 and James A. Mastrianni1*

Departments of Neurology,1 Pathology, The University of Chicago, 5841 Maryland Ave., Chicago, Illinois 606372

Received 2 October 2006/ Accepted 6 December 2006

Prion diseases are transmissible neurodegenerative diseases caused by a conformational isoform of the prion protein (PrP), a host-encoded cell surface sialoglycoprotein. Recent evidence suggests a cytosolic fraction of PrP (cyPrP) functions either as an initiating factor or toxic element of prion disease. When expressed in cultured cells, cyPrP acquires properties of the infectious conformation of PrP (PrPSc), including insolubility, protease resistance, aggregation, and toxicity. Transgenic mice (2D1 and 1D4 lines) that coexpress cyPrP and PrPC exhibit focal cerebellar atrophy, scratching behavior, and gait abnormalities suggestive of prion disease, although they lack protease-resistant PrP. To determine if the coexpression of PrPC is necessary or inhibitory to the phenotype of these mice, we crossed Tg1D4(Prnp+/+) mice with PrP-ablated mice (TgPrnpo/o) to generate Tg1D4(Prnpo/o) mice and followed the development of disease and pathological phenotype. We found no difference in the onset of symptoms or the clinical or pathological phenotype of disease between Tg1D4(Prnp+/+) and Tg1D4(Prnpo/o) mice, suggesting that cyPrP and PrPC function independently in the disease state. Additionally, Tg1D4(Prnpo/o) mice were resistant to challenge with mouse-adapted scrapie (RML), suggesting cyPrP is inaccessible to PrPSc. We conclude that disease phenotype and cellular toxicity associated with the expression of cyPrP are independent of PrPC and the generation of typical prion disease.

* Corresponding author. Mailing address: Department of Neurology, University of Chicago, MC2030, 5841 South Maryland Ave., Chicago, IL 60637. Phone: (773) 834-3975. Fax: (773) 702-2976. E-mail: jmastria{at}uchicago.edu.

{triangledown} Published ahead of print on 20 December 2006.

Journal of Virology, March 2007, p. 2831-2837, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02157-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lund, C., Olsen, C. M., Skogtvedt, S., Tveit, H., Prydz, K., Tranulis, M. A. (2009). Alternative Translation Initiation Generates Cytoplasmic Sheep Prion Protein. J. Biol. Chem. 284: 19668-19678 [Abstract] [Full Text]  


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