Defining the conformational features of anchorless, poorly neuroinvasive prions.
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 infecti...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3630170?pdf=render |
| _version_ | 1818155610250674176 |
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| author | Cyrus Bett Tim D Kurt Melanie Lucero Margarita Trejo Annemieke J Rozemuller Qingzhong Kong K Peter R Nilsson Eliezer Masliah Michael B Oldstone Christina J Sigurdson |
| author_facet | Cyrus Bett Tim D Kurt Melanie Lucero Margarita Trejo Annemieke J Rozemuller Qingzhong Kong K Peter R Nilsson Eliezer Masliah Michael B Oldstone Christina J Sigurdson |
| author_sort | Cyrus Bett |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T14:45:08Z |
| format | Article |
| id | doaj.art-26526db1ef1344248a306b62cee33ac9 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-11T14:45:08Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-26526db1ef1344248a306b62cee33ac92022-12-22T01:01:43ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-01-0194e100328010.1371/journal.ppat.1003280Defining the conformational features of anchorless, poorly neuroinvasive prions.Cyrus BettTim D KurtMelanie LuceroMargarita TrejoAnnemieke J RozemullerQingzhong KongK Peter R NilssonEliezer MasliahMichael B OldstoneChristina J SigurdsonInfectious 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.http://europepmc.org/articles/PMC3630170?pdf=render |
| spellingShingle | Cyrus Bett Tim D Kurt Melanie Lucero Margarita Trejo Annemieke J Rozemuller Qingzhong Kong K Peter R Nilsson Eliezer Masliah Michael B Oldstone Christina J Sigurdson Defining the conformational features of anchorless, poorly neuroinvasive prions. PLoS Pathogens |
| title | Defining the conformational features of anchorless, poorly neuroinvasive prions. |
| title_full | Defining the conformational features of anchorless, poorly neuroinvasive prions. |
| title_fullStr | Defining the conformational features of anchorless, poorly neuroinvasive prions. |
| title_full_unstemmed | Defining the conformational features of anchorless, poorly neuroinvasive prions. |
| title_short | Defining the conformational features of anchorless, poorly neuroinvasive prions. |
| title_sort | defining the conformational features of anchorless poorly neuroinvasive prions |
| url | http://europepmc.org/articles/PMC3630170?pdf=render |
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