Abstract

Prions are the proteinaceous infectious agents responsible for Transmissible Spongiform Encephalopathies. Compelling evidence supports the hypothesis that prions are composed exclusively of a misfolded version of the prion protein (PrPSc) that replicates in the body in the absence of nucleic acids by inducing the misfolding of the cellular prion protein (PrPC). The most common form of human prion disease is sporadic, which appears to have its origin in a low frequency event of spontaneous misfolding to generate the first PrPSc particle that then propagates as in the infectious form of the disease. The main goal of this study was to mimic an early event in the etiology of sporadic disease by attempting de novo generation of infectious PrPSc in vitro. For this purpose we analyzed in detail the possibility of spontaneous generation of PrPSc by the protein misfolding cyclic amplification (PMCA) procedure. Under standard PMCA conditions, and taking precautions to avoid cross-contamination, de novo generation of PrPSc was never observed, supporting the use of the technology for diagnostic applications. However, we report that PMCA can be modified to generate PrPSc in the absence of pre-existing PrPSc in different animal species at a low and variable rate. De novo generated PrPSc was infectious when inoculated into wild type hamsters, producing a new disease phenotype with unique clinical, neuropathological and biochemical features. Our results represent additional evidence in support of the prion hypothesis and provide a simple model to study the mechanism of sporadic prion disease. The findings also suggest that prion diversity is not restricted to those currently known, and that likely new forms of infectious protein foldings may be produced, resulting in novel disease phenotypes.

Highlights

  • Prions are the proteinaceous infectious agents responsible for Transmissible Spongiform Encephalopathies (TSEs), a group of fatal neurodegenerative disorders, including Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy in cattle and chronic wasting disease in deer [1]

  • Prions are the unprecedented infectious agent associated with prion diseases, which are composed exclusively of a misfolded protein

  • In this study we report the de novo formation of infectious prion protein in vitro, which when inoculated into wild type animals is able to induce a new disease phenotype with unique clinical, neuropathological and biochemical characteristics

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Summary

Introduction

Prions are the proteinaceous infectious agents responsible for Transmissible Spongiform Encephalopathies (TSEs), a group of fatal neurodegenerative disorders, including Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy in cattle and chronic wasting disease in deer [1]. Recent studies have reported in vitro generation of infectious material by inducing or amplifying PrP misfolding, providing strong support for the prion hypothesis [3,4,5]. In addition of the infectious origin, TSEs can be inherited or appear sporadically. The latter is the most common origin in humans, in which there are no known infectious source and no evidence of the disease in the prior or subsequent generations of the patient’s family. It is thought that sporadic TSEs arise from the low frequency, spontaneous misfolding of the prion protein which propagates to other PrPC molecules in a manner similar as in the infectious cases

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