Accelerated high fidelity prion amplification within and across prion species barriers

Experimental obstacles have impeded our ability to study prion transmission within and, more particularly, between species. Here, we used cervid prion protein expressed in brain extracts of transgenic mice, referred to as Tg(CerPrP), as a substrate for in vitro generation of chronic wasting disease...

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Bibliographic Details
Published in:PLoS pathogens 2008-08, Vol.4 (8), p.e1000139-e1000139
Main Authors: Green, Kristi M, Castilla, Joaquín, Seward, Tanya S, Napier, Dana L, Jewell, Jean E, Soto, Claudio, Telling, Glenn C
Format: Article
Language:English
Subjects:
Animals
Brain
Creutzfeldt-Jakob disease
Deer
Development and progression
Disease transmission
Distribution
Female
Genetic aspects
Immunization
Infectious Diseases/Prion Diseases
Mice
Mice, Transgenic
Pathogenesis
Physiological aspects
Prion diseases
Prions
Prions - metabolism
Protein Folding
Proteins
Public health
Risk factors
Sheep
Species Specificity
Spongiform encephalopathies
Studies
Wasting Disease, Chronic - metabolism
Wasting Disease, Chronic - pathology
Wasting Disease, Chronic - transmission
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Summary:Experimental obstacles have impeded our ability to study prion transmission within and, more particularly, between species. Here, we used cervid prion protein expressed in brain extracts of transgenic mice, referred to as Tg(CerPrP), as a substrate for in vitro generation of chronic wasting disease (CWD) prions by protein misfolding cyclic amplification (PMCA). Characterization of this infectivity in Tg(CerPrP) mice demonstrated that serial PMCA resulted in the high fidelity amplification of CWD prions with apparently unaltered properties. Using similar methods to amplify mouse RML prions and characterize the resulting novel cervid prions, we show that serial PMCA abrogated a transmission barrier that required several hundred days of adaptation and subsequent stabilization in Tg(CerPrP) mice. While both approaches produced cervid prions with characteristics distinct from CWD, the subtly different properties of the resulting individual prion isolates indicated that adaptation of mouse RML prions generated multiple strains following inter-species transmission. Our studies demonstrate that combined transgenic mouse and PMCA approaches not only expedite intra- and inter-species prion transmission, but also provide a facile means of generating and characterizing novel prion strains.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1000139