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Glycans are not necessary to maintain the pathobiological features of bovine spongiform encephalopathy
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Edité par CCSD ; Public Library of Science -
International audience. Abstract:The role of the glycosylation status of PrPC in the conversion to its pathological counterpart and on cross-species transmission of prion strains has been widely discussed. Here, we assessed the effect on strain characteristics of bovine spongiform encephalopathy (BSE) isolates with different transmission histories upon propagation on a model expressing a non-glycosylated human PrPC. Bovine, ovine and porcine-passaged BSE, and variant Creutzfeldt-Jakob disease (vCJD) isolates were used as seeds/inocula in both in vitro and in vivo propagation assays using the non-glycosylated human PrPC-expressing mouse model (TgNN6h). After protein misfolding cyclic amplification (PMCA), all isolates maintained the biochemical characteristics of BSE. On bioassay, all PMCA-propagated BSE prions were readily transmitted to TgNN6h mice, in agreement with our previous in vitro results. TgNN6h mice reproduced the characteristic neuropathological and biochemical hallmarks of BSE, suggesting that the absence of glycans did not alter the pathobiological features of BSE prions. Moreover, back-passage of TgNN6h-adapted BSE prions to BoTg110 mice recovered the full BSE phenotype, confirming that the glycosylation of human PrPC is not essential for the preservation of the human transmission barrier for BSE prions or for the maintenance of BSE strain properties.Author summary:Bovine spongiform encephalopathy (BSE), publicly known as "mad cow disease", is a neurodegenerative disorder affecting cattle, caused by unconventional agents called prions. BSE can naturally transmit to human beings, producing the variant form of Creutzfeldt-Jakob disease (vCJD), which caused an unprecedented health and economic crisis in the UE. Prions are composed of PrPSc, a misfolded form of the cellular protein PrPC, which can be variably glycosylated by conjugation with sugar molecules at two positions of its sequence. Several studies reported the role of PrPC-attached sugars on important aspects of prion biology, such as the existence of different prion strains. Here, we demonstrate that it is possible to propagate BSE prions (from different animal and human sources) in a non-glycosylated human PrPC environment without loss of their strain properties. Different BSE isolates were successfully transmitted to a transgenic mouse model expressing non-glycosylated human PrPC, and these animals manifested neuropathological and biochemical signs compatible with BSE. To definitely prove the maintenance of the strain, non-glycosylated BSE prions were transmitted to their original host: transgenic mice expressing cattle PrPC. These animals recovered the full BSE phenotype, confirming that the glycosylation of human PrPC is not relevant for the propagation of this particular prion strain.
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