The Prion Protein Preference of Sporadic Creutzfeldt-Jakob Disease Subtypes

Helen M.J Klemm,Jeremy M Welton,Colin L Masters,Genevieve M Klug,Alison Boyd,Andrew F Hill,Steven J Collins,Victoria A Lawson

doi:10.1074/jbc.m112.368803

Abstract

Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes.

Highlights

Sporadic Creutzfeldt-Jakob disease (CJD) encompasses a spectrum of clinical phenotypes, the origin of which has not been fully elucidated
Cell-free Propagation of PrPC into a protease-resistant form (PrPres) by the Protease-resistant Core of PrPSc—A cell-free, in vitro, conversion activity assay (CAA) was used to determine the conversion activity of a particular PrPC substrate when presented with a PrPSc seed derived from a prion-infected brain homogenate
A simple cell-free CAA was used to investigate the role of the polymorphism at codon 129 of prion protein gene (PRNP) and brainderived environment on the de novo generation of PrPres from Sporadic Creutzfeldt-Jakob disease (sCJD) PrPSc molecular subtype

Summary

Introduction

Sporadic Creutzfeldt-Jakob disease (CJD) encompasses a spectrum of clinical phenotypes, the origin of which has not been fully elucidated. Results: Cell-free prion protein misfolding by sporadic CJD subtypes was affected by brain tissue composition and not related to absolute levels of PrPC. Conclusion: Tissue environment contributes to CJD subtype-specific prion protein misfolding. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrPC). The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes

Objectives

Results

Conclusion