Oral Ingestion of Synthetically Generated Recombinant Prion Is Sufficient to Cause Prion Disease in Wild-Type Mice.

Jiyan Ma,Xiangyi Zhang,Chenhua Pan,Guohua Yu,Chonggang Yuan,Junwei Yang,Shunxiong Wei,Ying Chen,Yi-Hsuan Pan

doi:10.3390/pathogens9080653

Jiyan Ma, Xiangyi Zhang + Show 7 more

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https://doi.org/10.3390/pathogens9080653

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Abstract

Prion disease is a group of transmissible neurodegenerative disorders affecting humans and animals. The prion hypothesis postulates that PrPSc, the pathogenic conformer of host-encoded prion protein (PrP), is the unconventional proteinaceous infectious agent called prion. Supporting this hypothesis, highly infectious prion has been generated in vitro with recombinant PrP plus defined non-protein cofactors and the synthetically generated prion (recPrPSc) is capable of causing prion disease in wild-type mice through intracerebral (i.c.) or intraperitoneal (i.p.) inoculation. Given that many of the naturally occurring prion diseases are acquired through oral route, demonstrating the capability of recPrPSc to cause prion disease via oral transmission is important, but has never been proven. Here we showed for the first time that oral ingestion of recPrPSc is sufficient to cause prion disease in wild-type mice, which was supported by the development of fatal neurodegeneration in exposed mice, biochemical and histopathological analyses of diseased brains, and second round transmission. Our results demonstrate the oral transmissibility of recPrPSc and provide the missing evidence to support that the in vitro generated recPrPSc recapitulates all the important properties of naturally occurring prions.

Highlights

Prion diseases, known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases including Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), and Kuru in humans, scrapie in sheep and goats, chronic wasting disease (CWD) in cervids, and bovine spongiform encephalopathy (BSE) in cattle [1,2]
Our study provided the first experimental evidence that oral feeding of recPrPSc is sufficient to cause
Because orally ingested prions are exposed to the digestion process

Summary

Introduction

Known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases including Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), and Kuru in humans, scrapie in sheep and goats, chronic wasting disease (CWD) in cervids, and bovine spongiform encephalopathy (BSE) in cattle [1,2]. Different from other late age onset neurodegenerative disorders, prion disease is a naturally occurring infectious disease that can be transmitted within and between species [2]. It is well established that in prion disease, the host-encoded PrP converts from its normal, soluble and protease sensitive PrPC form to the disease-associated, aggregated and protease resistant PrPSc conformer [3]. The prion hypothesis posits that PrPSc is the infectious agent and because of its seeding capability, PrPSc is able to seed the conversion of host-encoded PrPC to. PrPSc , resulting in prion disease [1]. PrPSctechnique is the infectious agent and of its seeding prions, capability, PrPScScisisable to seed thehighly conversion (sPMCA). Similar to because naturally occurring recPrP aggregated, resistant

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