Regulating Factors of PrPres Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains

Etienne Levavasseur,Stéphane Haïk,Véronique Sazdovitch,Émilie Morain,Baptiste A Faucheux,Nicolas Privat,Jean-Jacques Hauw,Jean-Philippe Brandel,Isabelle Laffont-Proust,Katell Peoc'H,Adriano Aguzzi

doi:10.1371/journal.pone.0002786

Abstract

ObjectiveThe glycoprofile of pathological prion protein (PrPres) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrPres always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrPres glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease.MethodsPrPres glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrPres.ResultsThe regional distribution of PrPres glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrPres glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrPres in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrPres was undistinguishable from that observed in variant CJD.InterpretationRegulations leading to variations of PrPres pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrPres may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD.

Highlights

Human prion diseases are fatal neurodegenerative diseases
Number of sporadic Creutzfeldt-Jakob disease (CJD) cases and variant CJD cases are distributed according to the genotype at codon 129 of polymorphisms within the gene encoding PrP (PRNP) (MM: methionine homozygote, VV: valine homozygote, MV: methionine-valine heterozygote) and partially protease-resistant isoform (PrPres) type
This study provides new insight into the analysis of PrPres heterogeneity within Sporadic Creutzfeldt-Jakob disease (sCJD) cases, based upon the biochemical analysis of at least 3 different brain regions from 123 sCJD cases

Summary

Introduction

A classification of PrPres Western blot patterns, obtained after proteinase K (PK) digestion which leads to PK-resistant core fragments of either 21 kDa (type 1) or 19 kDa (type 2), has been proposed [4] This difference results from distinct PK cleavage sites of PrPres [5]. By correlating codon 129 genotypes and PrPres types to clinical and pathological features in a series of 300 sporadic CJD, six molecular combinations corresponding to some phenotypic variants were identified [7]. These observations are based on the postulate that the same PrP conformer accumulates in the whole brain [8]. While PrPres glycosylation is a key factor in strain diagnosis and probably brain targeting in human diseases, whether it is regulated between brain regions, and how, remains largely unknown

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Conclusion