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

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.

Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes

“…Meanwhile, intravenous transmission of BSE is as efficient as the intracerebral inoculation (29). We reported previously that knock-in mice expressing human PrP with heterozygosity for glutamine/lysine at another polymorphic codon 219 (219E/K) are susceptible to vCJD prions (28). Indeed, two vCJD patients with the 219E/K genotype were reported subsequently (30).…”

Heterozygous inhibition in prion infection

“…1). 11 Moreover, the amount of PrP Sc in Ki-Hu129M/V mice was even lower than that in hemizygous knock-in mice expressing human PrP 129M from one allele (Ki-Hu129M/0), which express half the level of PrP 129M compared with Ki-Hu129M/M mice. Thus, we confirmed that the decreased PrP Sc accumulation in Ki-Hu129M/V mice was not due only to the expression level of PrP 129M.…”

“…10,11 To explain this heterozygous inhibition, we propose a possible mechanism designated as the stone fence model.…”

Insights into prion biology

“…28,117,125,135 In contrast, PrP Q219K, like, Sup35 G58D, converts to the prion conformer efficiently, destabilizes aggregates and is incompatible only with prion variants of reduced thermodynamic stability. 28,105,117,125,126 Thus, despite the distinct cellular environments in which mammalian and yeast prions propagate, the pathways of dominant inhibition that we have uncovered for Sup35 mutants may be applicable to PrP mutants and may provide mechanistic insight into the phenotypic outcomes of prion infections in that system.…”

“…[96][97][98][99][100][101][102][103][104][105] These polymorphisms clearly restrict the range of conformations accessible to the prion and therefore its ability to replicate certain variants. 31,43,[106][107][108][109][110] However, many of the same sequence changes also function as dominant inhibitors of prion propagation in vivo, 105,[111][112][113][114][115][116][117][118] and a similar effect occurs upon co-expression of PrP homologues from different species. 79,[119][120][121][122][123][124] Thus, these sequence variants must target crucial events in prion propagation by the wildtype protein, and elucidating their mechanisms of action could be instructive for developing therapeutic interventions for these diseases.…”