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Zerui Wang, Jue Yuan, Pingping Shen, Romany Abskharon, Yue Lang, Johnny Dang, Alise Adornato, Ling Xu, Jiafeng Chen, Jiachun Feng, Mohammed Moudjou, Tetsuyuki Kitamoto, Jan Langeveld, Brian Appleby, Jiyan Ma, Qingzhong Kong, Robert B. Petersen, Wen Quan Zou*, Li Cui
Research output: Contribution to journal › Article › Academic › peer-review
Both sporadic variably protease-sensitive prionopathy (VPSPr) and familial Creutzfeldt-Jakob disease linked to the prion protein (PrP) V180I mutation (fCJDV180I) have been found to share a unique pathological prion protein (PrPSc) that lacks the protease-resistant PrPSc glycosylated at residue 181 because two of four PrP glycoforms are apparently not converted into the PrPSc from their cellular PrP (PrPC). To investigate the seeding activity of these unique PrPSc molecules, we conducted in vitro prion conversion experiments using serial protein misfolding cyclic amplification (sPMCA) and real-time quaking-induced conversion (RT-QuIC) assays with different PrPC substrates. We observed that the seeding of PrPSc from VPSPr or fCJDV180I in the sPMCA reaction containing normal human or humanized transgenic (Tg) mouse brain homogenates generated PrPSc molecules that unexpectedly exhibited a dominant diglycosylated PrP isoform along with PrP monoglycosylated at residue 181. The efficiency of PrPSc amplification was significantly higher in non-CJDMM than in non-CJDVV human brain homogenate, whereas it was higher in normal TgVV than in TgMM mouse brain homogenate. PrPC from the mixture of normal TgMM and Tg mouse brain expressing PrPV180I mutation (Tg180) but not TgV180I alone was converted into PrPSc by seeding with the VPSPr or fCJDV180I. The RT-QuIC seeding activity of PrPSc from VPSPr and fCJDV180I was significantly lower than that of sCJD. Our results suggest that the formation of glycoform-selective prions may be associated with an unidentified factor in the affected brain and the glycoform-deficiency of PrPSc does not affect the glycoforms of in vitro newly amplified PrPSc.
Original language | English |
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Pages (from-to) | 5456-5469 |
Journal | Molecular Neurobiology |
Volume | 56 |
Issue number | 8 |
Early online date | 5 Jan 2019 |
DOIs | |
Publication status | Published - Aug 2019 |
Research output: Contribution to journal › Comment/Letter to the editor › Academic