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J. Virol. doi:10.1128/JVI.02157-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cytosolic Prion Protein Toxicity is Independent of Cellular Prion Protein Expression and Prion Propagation

Departments of Neurology and Pathology, The University of Chicago, 5841 Maryland Ave., Chicago, IL 60637

	Abstract

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 (PrP^Sc), including insolubility, protease resistance, aggregation, and toxicity. Transgenic mice (2D1 and 1D4 lines) that co-express cyPrP and PrP^C exhibit focal cerebellar atrophy, scratching behavior, and gait abnormalities, suggestive of prion disease, although they lack protease-resistant PrP. To determine if the co-expression of PrP^C is necessary or inhibitory to the phenotype of these mice, we crossed Tg1D4Prnp^+/+ mice with PrP ablated mice (TgPrnp^o/o) to generate Tg1D4Prnp^o/o mice, and followed the development of disease and pathologic phenotype. We found no difference in the onset of symptoms nor the clinical or pathologic phenotype of disease between Tg1D4Prnp^+/+ and Tg1D4Prnp^o/o mice, suggesting that cyPrP and PrP^C function independently in the disease state. Additionally, Tg1D4Prnp^o/o mice were resistant to challenge with mouse-adapted scrapie (RML), suggesting cyPrP is inaccessible to PrP^Sc. We conclude that disease phenotype and cellular toxicity associated with the expression of cyPrP is independent of PrP^C and the generation of typical prion disease.