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Defining the Confor...
Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions
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- Bett, Cyrus (author)
- Department of Pathology, University of California, San Diego, La Jolla, California, United States of America
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- Kurt, Tim D. (author)
- Department of Pathology, University of California, San Diego, La Jolla, California, United States of America
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- Lucero, Melanie (author)
- Department of Pathology, University of California, San Diego, La Jolla, California, United States of America
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- Trejo, Margarita (author)
- Department of Neuroscience, University of California, San Diego, La Jolla, California, United States of America
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- Rozemuller, Annemieke J. (author)
- Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands
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- Kong, Qingzhong (author)
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America
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- Nilsson, Peter (author)
- Linköpings universitet,Kemi,Tekniska högskolan
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- Masliah, Eliezer (author)
- Department of Neuroscience, University of California, San Diego, La Jolla, California, United States of America
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- Oldstone, Michael B. (author)
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
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- Sigurdson, Christina J. (author)
- Department of Pathology, Immunology, and Microbiology, University of California, Davis, Davis, California, United States of America
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(creator_code:org_t)
- 2013-04-18
- 2013
- English.
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In: PLoS Pathogens. - : Public Library of Science. - 1553-7366 .- 1553-7374. ; 9:4
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Abstract
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- Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion.
Keyword
- TECHNOLOGY
- TEKNIKVETENSKAP
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Bett, Cyrus
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Kurt, Tim D.
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Lucero, Melanie
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Trejo, Margarita
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Rozemuller, Anne ...
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Kong, Qingzhong
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show more...
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Nilsson, Peter
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Masliah, Eliezer
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Oldstone, Michae ...
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Sigurdson, Chris ...
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- Articles in the publication
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PLoS Pathogens
- By the university
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Linköping University