Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease
The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately...
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Public Library of Science
2011
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228811/ |
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pubmed-32288112011-12-05 Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease Makarava, Natallia Kovacs, Gabor G. Savtchenko, Regina Alexeeva, Irina Budka, Herbert Rohwer, Robert G. Baskakov, Ilia V. Research Article The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrPSc template. Here we report that authentic PrPSc and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrPSc and lack any detectable PrPSc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrPSc evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrPSc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as “deformed templating” postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrPSc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases. Public Library of Science 2011-12-01 /pmc/articles/PMC3228811/ /pubmed/22144901 http://dx.doi.org/10.1371/journal.ppat.1002419 Text en Makarava et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Makarava, Natallia Kovacs, Gabor G. Savtchenko, Regina Alexeeva, Irina Budka, Herbert Rohwer, Robert G. Baskakov, Ilia V. |
| spellingShingle |
Makarava, Natallia Kovacs, Gabor G. Savtchenko, Regina Alexeeva, Irina Budka, Herbert Rohwer, Robert G. Baskakov, Ilia V. Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease |
| author_facet |
Makarava, Natallia Kovacs, Gabor G. Savtchenko, Regina Alexeeva, Irina Budka, Herbert Rohwer, Robert G. Baskakov, Ilia V. |
| author_sort |
Makarava, Natallia |
| title |
Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease |
| title_short |
Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease |
| title_full |
Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease |
| title_fullStr |
Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease |
| title_full_unstemmed |
Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease |
| title_sort |
genesis of mammalian prions: from non-infectious amyloid fibrils to a transmissible prion disease |
| description |
The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrPSc template. Here we report that authentic PrPSc and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrPSc and lack any detectable PrPSc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrPSc evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrPSc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as “deformed templating” postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrPSc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases. |
| publisher |
Public Library of Science |
| publishDate |
2011 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228811/ |
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1611491325925916672 |