Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease

Author:

Galeno Roberta1,Di Bari Michele Angelo2,Nonno Romolo2,Cardone Franco1,Sbriccoli Marco1,Graziano Silvia1,Ingrosso Loredana1,Fiorini Michele3,Valanzano Angelina1,Pasini Giulia3,Poleggi Anna1,Vinci Ramona1,Ladogana Anna1,Puopolo Maria1,Monaco Salvatore3,Agrimi Umberto2,Zanusso Gianluigi3,Pocchiari Maurizio1

Affiliation:

1. Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy

2. Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy

3. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy

Abstract

ABSTRACT In 2007, we reported a patient with an atypical form of Creutzfeldt-Jakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrP TSE ) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrP TSE MV AG ), showing that PrP TSE MV AG is composed of multiple conformers with biochemical properties distinct from those of PrP TSE type 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MV AG to bank voles and gene-targeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrP TSE deposition patterns, and PrP TSE glycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MV AG . IMPORTANCE Sporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission.

Funder

Ministero della Salute

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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