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

Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W.; Mohri, Satoshi; Kitamoto, Tetsuyuki

doi:10.1074/jbc.m113.470328

Cited by 16 publications

(31 citation statements)

References 34 publications

(36 reference statements)

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“…Our approach, focusing on PK-treated PrP Sc , did not allow us to address in depth the issue of the influence of this putative "fully PK-sensitive PrP Sc " on thermostability profile; nevertheless, the lack of an obvious correlation between sedimentation profile (as determined in reference 27) and thermostability (present work) of PK-treated PrP Sc suggests that factors other than size also contribute to the thermostability of PrP Sc aggregates in CJD. The present results, when combined with the growing knowledge on human prion strains, provide novel insights into the relationships between the physicochemical properties of PrP Sc aggregates and disease characteristics such as incidence, phenotypic expression, and transmission properties (5,7,8,10,11,(48)(49)(50). In particular, PrP Sc thermostability appears to largely, although not entirely, correlate with prion replication efficiency expressed either by the attack rate and incubation time after experimental transmission in the most compatible host genotype or by the relative incidence and duration of clinical disease (Table 2).…”

Section: Given That Prpmentioning

confidence: 76%

Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

Cescatti

Saverioni

Capellari

et al. 2016

J Virol

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The wide phenotypic variability of prion diseases is thought to depend on the interaction of a host genotype with prion strains that have self-perpetuating biological properties enciphered in distinct conformations of the misfolded prion protein PrP Sc . This concept is largely based on indirect approaches studying the effect of proteases or denaturing agents on the physicochemical properties of PrP Sc aggregates. Furthermore, most data come from studies on rodent-adapted prion strains, making current understanding of the molecular basis of strains and phenotypic variability in naturally occurring diseases, especially in humans, more limited. To fill this gap, we studied the effects of guanidine hydrochloride (GdnHCl) and heating on PrP Sc aggregates extracted from 60 sporadic Creutzfeldt-Jakob disease (CJD) and 6 variant CJD brains. While denaturation curves obtained after exposure of PrP Sc to increasing GdnHCl concentrations showed similar profiles among the 7 CJD types analyzed, PrP Sc exposure to increasing temperature revealed significantly different and type-specific responses. In particular, MM1 and VV2, the most prevalent and fast-replicating CJD types, showed stable and highly resistant PrP Sc aggregates, whereas VV1, a rare and slowly propagating type, revealed unstable aggregates that easily dissolved at low temperature. Taken together, our results indicate that the molecular interactions mediating the aggregation state of PrP Sc , possibly enciphering strain diversity, are differently targeted by GdnHCl, temperature, and proteases. Furthermore, the detected positive correlation between the thermostability of PrP Sc aggregates and disease transmission efficiency makes inconsistent the proposed hypothesis that a decrease in conformational stability of prions results in an increase in their replication efficiency. IMPORTANCEPrion strains are defined as infectious isolates propagating distinctive phenotypic traits after transmission to syngeneic hosts. Although the molecular basis of prion strains is not fully understood, it is largely accepted that variations in prion protein conformation drive the molecular changes leading to the different phenotypes. In this study, we exposed abnormal prion protein aggregates encompassing the spectrum of human prion strains to both guanidine hydrochloride and thermal unfolding. Remarkably, while exposure to increasing temperature revealed significant strain-specific differences in the denaturation profile of the protein, treatment with guanidine hydrochloride did not. The findings suggest that thermal and chemical denaturation perturb the structure of prion protein aggregates differently. Moreover, since the most thermostable prion protein types were those associated with the most prevalent phenotypes and most rapidly and efficiently transmitting strains, the results suggest a direct correlation between strain replication efficiency and the thermostability of prion protein aggregates. P rion diseases are invariably fatal neurodegenerative disorders of humans ...

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Section: Given That Prpmentioning

confidence: 76%

Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

Cescatti

Saverioni

Capellari

et al. 2016

J Virol

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“…Of note, the attack rates gradually decreased from 129M/M to 129M/V to 129V/V mice, and the 129M/M mice showed the shortest incubation periods among the three mouse lines (Table 1; Fig. 2a) [75]. These results suggest that 129M/V heterozygotes and 129V/V homozygotes are not entirely resistant against secondary vCJD infection and may develop disease after prolonged incubation periods.…”

Section: Gcjd Gss and Ffimentioning

confidence: 85%

“…This finding raises the possibility that 129V/V homozygotes may also be highly susceptible to gCJD-V180I because the disease susceptibility of the PRNP heterozygotes usually does not exceed that of homozygotes for the susceptible allele [6,29,34,37,41,75]. Although we could not test this possibility further because of the extremely low prevalence of the 129V/V genotype in Japan, 129V/V homozygotes have been overrepresented in VPSPr [68].…”

Section: Unsolved Mysteriesmentioning

confidence: 91%

“…These transmission data suggest the existence of a significant species barrier between cattle and humans, and may explain the low number of vCJD cases in the human population [5]. By contrast, in experimental transmission of vCJD prions as an experimental model of secondary vCJD infection, all three codon 129 genotypes showed susceptibility [5,75]. Of note, the attack rates gradually decreased from 129M/M to 129M/V to 129V/V mice, and the 129M/M mice showed the shortest incubation periods among the three mouse lines (Table 1; Fig.…”

Section: Gcjd Gss and Ffimentioning

confidence: 92%

“…[75] Human growth hormone (hGH) obtained from cadaveric pituitary is another major source of iatrogenic transmission of CJD [8]. In hGH-associated CJD patients in France and the United States, 129M/M homozygotes and 129V/V homozygotes have been overrepresented, while 129M/V heterozygotes have been underrepresented [7,8].…”

Section: Iatrogenic Cjd and Kurumentioning

confidence: 99%

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The influence of PRNP polymorphisms on human prion disease susceptibility: an update

et al. 2015

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Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Sträussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.

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A novel subtype of sporadic Creutzfeldt–Jakob disease with PRNP codon 129MM genotype and PrP plaques

Bayazid,

Orru’,

Aslam

et al. 2023

Acta Neuropathol

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The presence of amyloid kuru plaques is a pathological hallmark of sporadic Creutzfeldt–Jakob disease (sCJD) of the MV2K subtype. Recently, PrP plaques (p) have been described in the white matter of a small group of CJD (p-CJD) cases with the 129MM genotype and carrying resPrPD type 1 (T1). Despite the different histopathological phenotype, the gel mobility and molecular features of p-CJD resPrPD T1 mimic those of sCJDMM1, the most common human prion disease. Here, we describe the clinical features, histopathology, and molecular properties of two distinct PrP plaque phenotypes affecting the gray matter (pGM) or the white matter (pWM) of sCJD cases with the PrP 129MM genotype (sCJDMM). Prevalence of pGM- and pWM-CJD proved comparable and was estimated to be ~ 0.6% among sporadic prion diseases and ~ 1.1% among the sCJDMM group. Mean age at onset (61 and 68 years) and disease duration (~ 7 months) of pWM- and pGM-CJD did not differ significantly. PrP plaques were mostly confined to the cerebellar cortex in pGM-CJD, but were ubiquitous in pWM-CJD. Typing of resPrPD T1 showed an unglycosylated fragment of ~ 20 kDa (T120) in pGM-CJD and sCJDMM1 patients, while a doublet of ~ 21–20 kDa (T121−20) was a molecular signature of pWM-CJD in subcortical regions. In addition, conformational characteristics of pWM-CJD resPrPD T1 differed from those of pGM-CJD and sCJDMM1. Inoculation of pWM-CJD and sCJDMM1 brain extracts to transgenic mice expressing human PrP reproduced the histotype with PrP plaques only in mice challenged with pWM-CJD. Furthermore, T120 of pWM-CJD, but not T121, was propagated in mice. These data suggest that T121 and T120 of pWM-CJD, and T120 of sCJDMM1 are distinct prion strains. Further studies are required to shed light on the etiology of p-CJD cases, particularly those of T120 of the novel pGM-CJD subtype.

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

Cited by 16 publications

References 34 publications

Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions

The influence of PRNP polymorphisms on human prion disease susceptibility: an update

A novel subtype of sporadic Creutzfeldt–Jakob disease with PRNP codon 129MM genotype and PrP plaques

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