Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent
Abstract Unlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 sub...
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2021
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oai:doaj.org-article:49816cda18ac44b7b8c29880c70453922021-12-02T14:03:58ZSensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent10.1038/s41598-021-83630-12045-2322https://doaj.org/article/49816cda18ac44b7b8c29880c70453922021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83630-1https://doaj.org/toc/2045-2322Abstract Unlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 substrates: 2 from transgenic mice expressing human prion protein (PrP) with either methionine (M) or valine (V) at position 129, and 1 from bank voles. Brain extracts representing the 5 major clinicopathological sCJD subtypes (MM1/MV1, MM2, MV2, VV1, and VV2) all triggered seeded PrPTSE amplification during serial PMCA with strong seed- and substrate-dependence. Remarkably, bank vole PrP substrate allowed the propagation of all sCJD subtypes with preservation of the initial molecular PrPTSE type. In contrast, PMCA in human PrP substrates was accompanied by a PrPTSE molecular shift during heterologous (M/V129) PMCA reactions, with increased permissiveness of V129 PrP substrate to in vitro sCJD prion amplification compared to M129 PrP substrate. Combining PMCA amplification sensitivities with PrPTSE electrophoretic profiles obtained in the different substrates confirmed the classification of 4 distinct major sCJD prion strains (M1, M2, V1, and V2). Finally, the level of sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved.Maxime BélondradeSimon NicotCharly MayranLilian Bruyere-OstellsFlorian AlmelaMichele A. Di BariEtienne LevavasseurJoel C. WattsChantal Fournier-WirthSylvain LehmannStéphane HaïkRomolo NonnoDaisy BougardNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021) |
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Medicine R Science Q Maxime Bélondrade Simon Nicot Charly Mayran Lilian Bruyere-Ostells Florian Almela Michele A. Di Bari Etienne Levavasseur Joel C. Watts Chantal Fournier-Wirth Sylvain Lehmann Stéphane Haïk Romolo Nonno Daisy Bougard Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent |
| description |
Abstract Unlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 substrates: 2 from transgenic mice expressing human prion protein (PrP) with either methionine (M) or valine (V) at position 129, and 1 from bank voles. Brain extracts representing the 5 major clinicopathological sCJD subtypes (MM1/MV1, MM2, MV2, VV1, and VV2) all triggered seeded PrPTSE amplification during serial PMCA with strong seed- and substrate-dependence. Remarkably, bank vole PrP substrate allowed the propagation of all sCJD subtypes with preservation of the initial molecular PrPTSE type. In contrast, PMCA in human PrP substrates was accompanied by a PrPTSE molecular shift during heterologous (M/V129) PMCA reactions, with increased permissiveness of V129 PrP substrate to in vitro sCJD prion amplification compared to M129 PrP substrate. Combining PMCA amplification sensitivities with PrPTSE electrophoretic profiles obtained in the different substrates confirmed the classification of 4 distinct major sCJD prion strains (M1, M2, V1, and V2). Finally, the level of sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved. |
| format |
article |
| author |
Maxime Bélondrade Simon Nicot Charly Mayran Lilian Bruyere-Ostells Florian Almela Michele A. Di Bari Etienne Levavasseur Joel C. Watts Chantal Fournier-Wirth Sylvain Lehmann Stéphane Haïk Romolo Nonno Daisy Bougard |
| author_facet |
Maxime Bélondrade Simon Nicot Charly Mayran Lilian Bruyere-Ostells Florian Almela Michele A. Di Bari Etienne Levavasseur Joel C. Watts Chantal Fournier-Wirth Sylvain Lehmann Stéphane Haïk Romolo Nonno Daisy Bougard |
| author_sort |
Maxime Bélondrade |
| title |
Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent |
| title_short |
Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent |
| title_full |
Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent |
| title_fullStr |
Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent |
| title_full_unstemmed |
Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent |
| title_sort |
sensitive protein misfolding cyclic amplification of sporadic creutzfeldt–jakob disease prions is strongly seed and substrate dependent |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/49816cda18ac44b7b8c29880c7045392 |
| work_keys_str_mv |
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