New Molecular Insight into Mechanism of Evolution of Mammalian Synthetic Prions
| Autor: | Irina Alexeeva, Regina Savtchenko, Natallia Makarava, Ilia V. Baskakov, Robert G. Rohwer |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gene isoform Genetically modified mouse PrPSc Proteins Prions animal diseases Hamster Scrapie Biology Fibril Article Prion Diseases Pathology and Forensic Medicine law.invention Mice 03 medical and health sciences law Cricetinae Animals Humans Mammals Strain (chemistry) Brain Virology nervous system diseases Cell biology 030104 developmental biology Recombinant DNA Endopeptidase K |
| Zdroj: | The American Journal of Pathology. 186:1006-1014 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2015.11.013 |
| Popis: | Previous studies established that transmissible prion diseases could be induced by in vitro -produced recombinant prion protein (PrP) fibrils with structures that are fundamentally different from that of authentic PrP scrapie isoform (PrP Sc ). To explain evolution of synthetic prions, a new mechanism referred to as deformed templating was introduced. Here, we asked whether an increase in expression level of the cellular form of PrP (PrP C ) speeds up the evolution of synthetic strains in vivo . We found that in transgenic mice that overexpress hamster PrP C , PrP C overexpression accelerated recombinant PrP fibril-induced conversion of PrP C to the abnormal proteinase K-resistant state, referred to as atypical PrPres, which was the first product of PrP C misfolding in vivo . However, overexpression of PrP C did not facilitate the second step of synthetic strain evolution-transition from atypical PrPres to PrP Sc , which is attributed to the stochastic nature of rare deformed templating events. In addition, the potential of atypical PrPres to interfere with replication of a short-incubation time prion strain was investigated. Atypical PrPres was found to interfere strongly with replication of 263K in vitro ; however, it did not delay prion disease in animals. The rate of deformed templating does not depend on the concentration of substrate and is hence more likely to be controlled by the intrinsic rate of conformational errors in templating alternative self-propagating states. |
| Databáze: | OpenAIRE |
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