期刊
PATHOGENS
卷 10, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/pathogens10050513
关键词
prions disease; Creutzfeldt-Jakob disease (CJD); variably protease-sensitive prionopathy (VPSPr); Gerstmann-Straussler-Scheinker (GSS); glycoform-selective prion formation; real-time quaking-induced conversion (RT-QuIC) assay
类别
资金
- National Institutes of Health [R01NS109532]
- CJD Foundation
- Centers for Disease Control and Prevention
- ALZ/ARUK/MJFF/Weston
- National Natural Science Foundation of China (NNSFC) [81671186]
This study reveals the formation process of ladder-like PrPSc in variably protease-sensitive prionopathy (VPSPr), emphasizing its association with basic pH conditions. The research findings suggest that the glycoform-selective PrPSc in VPSPr is characterized by altered glycosylation and exhibits lower aggregation seeding activity compared to PrPSc in sporadic CJD (sCJD).
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-Straussler-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.
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