In Vitro Seeding Activity of Glycoform-Deficient Prions from Variably Protease-Sensitive Prionopathy and Familial CJD Associated with PrPV180I Mutation
Year: 2019
Type: article
Abstract: Both sporadic variably protease-sensitive prionopathy (VPSPr) and familial Creutzfeldt-Jakob disease linked to the prion protein (PrP) V180I mutation (fCJD V180I ) have been found to share a unique pathological prion protein (PrP Sc ) that lacks the protease-resistant PrP Sc glycosylated at residue 181 because two of four PrP glycoforms are apparently not converted into the PrP Sc from their cellular PrP (PrP C ). To investigate the seeding activity of these unique PrP Sc 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 PrP C substrates. We observed that the seeding of PrP Sc from VPSPr or fCJD V180I in the sPMCA reaction containing normal human or humanized transgenic (Tg) mouse brain homogenates generated PrP Sc molecules that unexpectedly exhibited a dominant diglycosylated PrP isoform along with PrP monoglycosylated at residue 181. The efficiency of PrP Sc 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. PrP C from the mixture of normal TgMM and Tg mouse brain expressing PrP V180I mutation (Tg180) but not TgV180I alone was converted into PrP Sc by seeding with the VPSPr or fCJD V180I . The RT-QuIC seeding activity of PrP Sc from VPSPr and fCJD V180I 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 PrP Sc does not affect the glycoforms of in vitro newly amplified PrP Sc .
Source: Molecular Neurobiology
Authors: Zerui Wang, Jue Yuan, Pingping Shen, Romany Abskharon, Yue Lang, Johnny Dang, Alise Adornato, Ling Xu, Jiafeng Chen, Jiachun Feng, Mohammed Moudjou, Tetsuyuki Kitamoto, Hyoung-gon Lee, Yong-Sun Kim, Jan Langeveld, Brian Appleby, Jiyan Ma, Qingzhong Kong, Robert B. Petersen, Wen-Quan Zou, Li Cui
Institutions: Jilin University, First Hospital of Jilin University, Case Western Reserve University, Van Andel Institute, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Virologie et Immunologie Moléculaires, Tohoku University, Texas State University, The University of Texas at San Antonio, Hallym University, Wageningen University & Research, University Hospitals of Cleveland, Central Michigan University, Chinese Center For Disease Control and Prevention, National Institute for Viral Disease Control and Prevention
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Awards: Role of skin prions in disease transmission and diagnostic testing of human prion disease, Generating iPSC-derived Neurons to Explore Formation & Inhibition of Human Prions, G3665056311, Study to establish the bioassay system for peripheral route infection of various prions, G7102455533, G8329257235, G9000102091
OpenAlex ID: W2907549190