Human Prion Protein (PrP) 219K Is Converted to PrPSc but Shows Heterozygous Inhibition in Variant Creutzfeldt-Jakob Disease Infection

Masaki Hizume,Atsushi Kobayashi,Kenta Teruya,Hiroaki Ohashi,James W Ironside,Shirou Mohri,Tetsuyuki Kitamoto

doi:10.1074/jbc.m809254200

Abstract

Prion protein gene (PRNP) E219K is a human polymorphism commonly occurring in Asian populations but is rarely found in patients with sporadic Creutzfeldt-Jakob disease (CJD). Thus the polymorphism E219K has been considered protective against sporadic CJD. The corresponding mouse prion protein (PrP) polymorphism variant (mouse PrP 218K) is not converted to the abnormal isoform (PrP(Sc)) and shows a dominant negative effect on wild-type PrP conversion. To define the conversion activity of this human molecule, we herein established knock-in mice with human PrP 219K and performed a series of transmission experiments with human prions. Surprisingly, the human PrP 219K molecule was converted to PrP(Sc) in variant CJD infection, and the conversion occurred more efficiently than PrP 219E molecule. Notably the knock-in mice with PRNP codon 219E/K showed the least efficient conversion compared with their hemizygotes with PRNP codon 219E/0 or codon 219K/0, or homozygotes with PRNP codon 219E/E or codon 219K/K. This phenomenon indicated heterozygous inhibition. This heterozygous inhibition was observed also in knock-in mice with PRNP codon 129M/V genotype. In addition to variant CJD infection, the human PrP 219K molecule is conversion-competent in transmission experiments with sporadic CJD prions. Therefore, the protective effect of PRNP E219K against sporadic CJD might be due to heterozygous inhibition.

Highlights

Human prion diseases have been classified into infectious, inherited, and sporadic forms
The human PrP contains 253 amino acids encoded by prion protein gene (PRNP), which is located on chromosome 20
We found that human PrP 219K is readily converted to PrPSc in variant CJD (vCJD) infection, and report the inhibition of PrP conversion in the heterozygous knock-in models

Summary

Introduction

Human prion diseases have been classified into infectious, inherited, and sporadic forms. The codon 218K variant (corresponding to the human 219K) in the murine prion protein gene (prnp) was not converted to PrPSc and showed a dominant negative effect on wild-type PrP conversion both in scrapie-infected neuroblastoma cells [15] and in transgenic mice [16]. We found that human PrP 219K is readily converted to PrPSc in vCJD infection, and report the inhibition of PrP conversion in the heterozygous knock-in models.

Results

Conclusion