Immunization with Recombinant Prion Protein Leads to Partial Protection in a Murine Model of TSEs through a Novel Mechanism

Konstantinos Xanthopoulos,Theodoros Sklaviadis,Minas Yiangou,Anastasia Kontana,Nikolaos Grigoriadis,Christos Panagiotidis,Christos Kyratsous,Rosa Lagoudaki,Corinne Ida Lasmezas

doi:10.1371/journal.pone.0059143

Konstantinos Xanthopoulos, Theodoros Sklaviadis + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0059143

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Abstract

Transmissible spongiform encephalopathies are neurodegenerative diseases, which despite fervent research remain incurable. Immunization approaches have shown great potential at providing protection, however tolerance effects hamper active immunization protocols. In this study we evaluated the antigenic potential of various forms of recombinant murine prion protein and estimated their protective efficacy in a mouse model of prion diseases. One of the forms tested provided a significant elongation of survival interval. The elongation was mediated via an acute depletion of mature follicular dendritic cells, which are associated with propagation of the prion infectious agent in the periphery and in part to the development of humoral immunity against prion protein. This unprecedented result could offer new strategies for protection against transmissible encephalopathies as well as other diseases associated with follicular dendritic cells.

Highlights

Transmissible spongiform encephalopathies (TSEs) or Prion diseases are invariably lethal neurodegenerative diseases, afflicting a wide range of hosts, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep and goats [1]
To prepare aggregated PrP, purified mrPrP inclusion bodies were suspended in sterile phosphate buffered saline (PBS) containing 0.05% Sarkosyl (Sigma) and the PrP content was estimated by densitometric analysis using Image J (v 1.46, available at http://rsbweb.nih.gov/ij/download.html) following SDS-PAGE and coomassie staining
To prepare solubilized PrP, mrPrP was further purified from the inclusion bodies, using Ni-NTA beads (Qiagen) according to the manufacturer’s instructions. mrPrP elution from the nickel beads was performed using 8 M urea, which was gradually diluted to 1 M

Summary

Introduction

Transmissible spongiform encephalopathies (TSEs) or Prion diseases are invariably lethal neurodegenerative diseases, afflicting a wide range of hosts, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep and goats [1]. PrPSc arises from the structural conversion of the cellular isoform of the prion protein (PrPC). The conversion of the cellular prion protein to the diseaseassociated isoform is a key point to the disease process, but has not yet been elucidated [4]. The two isoforms share the same primary structure and only differ in their secondary structure; PrPC is ahelices rich, whereas in PrPSc the percentage of b-pleated sheets is elevated. This structural difference leads to changes in resistance to proteinase K proteolysis (PrPSc is partially resistant) and solubility (PrPSc is insoluble) [1].Oxidation of some methionine residues in PrPSc is the only post translation chemical modification reported [5]

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