Further characterization of glycoform-selective prions of variably protease-sensitive prionopathy
Prion is an infectious protein (PrPSc ) that is derived from a cellular glycoprotein (PrPC ) through a conformational transition and associated with a group of prion diseases in animals and humans. Characterization of proteinase K (PK)-resistant PrPSc 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 PrPSc in variably protease-sensitive prionopathy (VPSPr) remain poorly understood. Here we reveal that formation of the ladder-like PrPSc in VPSPr is a PK-dependent two-step process, which is enhanced by basic pH. Two sets of PrPSc 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 PrPSc-seeding activity is lower and its lag time is longer in VPSPr than in sCJD. Our results suggest that the glycoform-selective PrPSc in VPSPr is associated with altered glycosylation, resulting in different PK-truncation and aggregation seeding activity compared to PrPSc in sCJD.
| Main Authors: | , , , , , , , , , |
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| Format: | Article/Letter to editor biblioteca |
| Language: | English |
| Subjects: | Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS), Glycoform-selective prion formation, Prions disease, Real-time quaking-induced conversion (RT-QuIC) assay, Variably protease-sensitive prionopathy (VPSPr), |
| Online Access: | https://research.wur.nl/en/publications/further-characterization-of-glycoform-selective-prions-of-variabl |
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