Prion Strain-Dependent Differences in Conversion of Mutant Prion Proteins in Cell Culture

Author:

Atarashi Ryuichiro12,Sim Valerie L.2,Nishida Noriyuki1,Caughey Byron2,Katamine Shigeru1

Affiliation:

1. Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 853-8523, Japan

2. Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840

Abstract

ABSTRACT Although the protein-only hypothesis proposes that it is the conformation of abnormal prion protein (PrP Sc ) that determines strain diversity, the molecular basis of strains remains to be elucidated. In the present study, we generated a series of mutations in the normal prion protein (PrP C ) in which a single glutamine residue was replaced with a basic amino acid and compared their abilities to convert to PrP Sc in cultured neuronal N2a58 cells infected with either the Chandler or 22L mouse-adapted scrapie strain. In mice, these strains generate PrP Sc of the same sequence but different conformations, as judged by infrared spectroscopy. Substitutions at codons 97, 167, 171, and 216 generated PrP C that resisted conversion and inhibited the conversion of coexpressed wild-type PrP in both Chandler-infected and 22L-infected cells. Interestingly, substitutions at codons 185 and 218 gave strain-dependent effects. The Q185R and Q185K PrP were efficiently converted to PrP Sc in Chandler-infected but not 22L-infected cells. Conversely, Q218R and Q218H PrP were converted only in 22L-infected cells. Moreover, the Q218K PrP exerted a potent inhibitory effect on the conversion of coexpressed wild-type PrP in Chandler-infected cells but had little effect on 22L-infected cells. These results show that two strains with the same PrP sequence but different conformations have differing abilities to convert the same mutated PrP C .

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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