Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy
Prion is an infectious protein (PrP<sup>Sc</sup>) that is derived from a cellular glycoprotein (PrP<sup>C</sup>) through a conformational transition and associated with a group of prion diseases in animals and humans. Characterization of proteinase K (PK)-resistant PrP<sup...
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MDPI AG
2021-04-01
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| author | Weiguanliu Zhang Xiangzhu Xiao Mingxuan Ding Jue Yuan Aaron Foutz Mohammed Moudjou Tetsuyuki Kitamoto Jan P. M. Langeveld Li Cui Wen-Quan Zou |
| author_facet | Weiguanliu Zhang Xiangzhu Xiao Mingxuan Ding Jue Yuan Aaron Foutz Mohammed Moudjou Tetsuyuki Kitamoto Jan P. M. Langeveld Li Cui Wen-Quan Zou |
| author_sort | Weiguanliu Zhang |
| collection | DOAJ |
| description | Prion is an infectious protein (PrP<sup>Sc</sup>) that is derived from a cellular glycoprotein (PrP<sup>C</sup>) through a conformational transition and associated with a group of prion diseases in animals and humans. Characterization of proteinase K (PK)-resistant PrP<sup>Sc</sup> by western blotting has been critical to diagnosis and understanding of prion diseases including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker (GSS) disease in humans. However, formation as well as biochemical and biological properties of the glycoform-selective PrP<sup>Sc</sup> in variably protease-sensitive prionopathy (VPSPr) remain poorly understood. Here we reveal that formation of the ladder-like PrP<sup>Sc</sup> in VPSPr is a PK-dependent two-step process, which is enhanced by basic pH. Two sets of PrP<sup>Sc</sup> fragments can be identified with antibodies directed against an intermediate or a C-terminal domain of the protein. Moreover, antibodies directed against specific PrP glycoforms reveal faster electrophoretic migrations of PrP fragments mono-glycosylated at residue 181 and 197 in VPSPr than those in sporadic CJD (sCJD). Finally, RT-QuIC assay indicates that PrP<sup>Sc</sup>-seeding activity is lower and its lag time is longer in VPSPr than in sCJD. Our results suggest that the glycoform-selective PrP<sup>Sc</sup> in VPSPr is associated with altered glycosylation, resulting in different PK-truncation and aggregation seeding activity compared to PrP<sup>Sc</sup> in sCJD. |
| first_indexed | 2024-03-10T12:01:54Z |
| format | Article |
| id | doaj.art-6fd16ee78a354f4f852a06da72790eb3 |
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| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-10T12:01:54Z |
| publishDate | 2021-04-01 |
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| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-6fd16ee78a354f4f852a06da72790eb32023-11-21T16:54:37ZengMDPI AGPathogens2076-08172021-04-0110551310.3390/pathogens10050513Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive PrionopathyWeiguanliu Zhang0Xiangzhu Xiao1Mingxuan Ding2Jue Yuan3Aaron Foutz4Mohammed Moudjou5Tetsuyuki Kitamoto6Jan P. M. Langeveld7Li Cui8Wen-Quan Zou9Department of Neurology, The First Hospital of Jilin University, Changchun 130000, ChinaDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USADepartment of Neurology, The First Hospital of Jilin University, Changchun 130000, ChinaDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USADepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USAMolecular Virology and Immunology Unit (VIM), Université Paris Saclay, INRAE, UVSQ, VIM, 78350 Jouy-en-Josas, FranceDepartment of Neurological Science, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, JapanDepartment of Infection Biology, Wageningen Bioveterinary Research, 8221RA 39 Lelystad, The NetherlandsDepartment of Neurology, The First Hospital of Jilin University, Changchun 130000, ChinaDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USAPrion is an infectious protein (PrP<sup>Sc</sup>) that is derived from a cellular glycoprotein (PrP<sup>C</sup>) through a conformational transition and associated with a group of prion diseases in animals and humans. Characterization of proteinase K (PK)-resistant PrP<sup>Sc</sup> by western blotting has been critical to diagnosis and understanding of prion diseases including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker (GSS) disease in humans. However, formation as well as biochemical and biological properties of the glycoform-selective PrP<sup>Sc</sup> in variably protease-sensitive prionopathy (VPSPr) remain poorly understood. Here we reveal that formation of the ladder-like PrP<sup>Sc</sup> in VPSPr is a PK-dependent two-step process, which is enhanced by basic pH. Two sets of PrP<sup>Sc</sup> fragments can be identified with antibodies directed against an intermediate or a C-terminal domain of the protein. Moreover, antibodies directed against specific PrP glycoforms reveal faster electrophoretic migrations of PrP fragments mono-glycosylated at residue 181 and 197 in VPSPr than those in sporadic CJD (sCJD). Finally, RT-QuIC assay indicates that PrP<sup>Sc</sup>-seeding activity is lower and its lag time is longer in VPSPr than in sCJD. Our results suggest that the glycoform-selective PrP<sup>Sc</sup> in VPSPr is associated with altered glycosylation, resulting in different PK-truncation and aggregation seeding activity compared to PrP<sup>Sc</sup> in sCJD.https://www.mdpi.com/2076-0817/10/5/513prions diseaseCreutzfeldt-Jakob disease (CJD)variably protease-sensitive prionopathy (VPSPr)Gerstmann-Sträussler-Scheinker (GSS)glycoform-selective prion formationreal-time quaking-induced conversion (RT-QuIC) assay |
| spellingShingle | Weiguanliu Zhang Xiangzhu Xiao Mingxuan Ding Jue Yuan Aaron Foutz Mohammed Moudjou Tetsuyuki Kitamoto Jan P. M. Langeveld Li Cui Wen-Quan Zou Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy Pathogens prions disease Creutzfeldt-Jakob disease (CJD) variably protease-sensitive prionopathy (VPSPr) Gerstmann-Sträussler-Scheinker (GSS) glycoform-selective prion formation real-time quaking-induced conversion (RT-QuIC) assay |
| title | Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy |
| title_full | Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy |
| title_fullStr | Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy |
| title_full_unstemmed | Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy |
| title_short | Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy |
| title_sort | further characterization of glycoform selective prions of variably protease sensitive prionopathy |
| topic | prions disease Creutzfeldt-Jakob disease (CJD) variably protease-sensitive prionopathy (VPSPr) Gerstmann-Sträussler-Scheinker (GSS) glycoform-selective prion formation real-time quaking-induced conversion (RT-QuIC) assay |
| url | https://www.mdpi.com/2076-0817/10/5/513 |
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