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

Kobayashi, Atsushi; Teruya, Kenta; Matsuura, Yuichi; Shirai, Tomoyuki; Nakamura, Yoshikazu; Yamada, Masahito; Mizusawa, Hidehiro; Mohri, Satoshi; Kitamoto, Tetsuyuki

doi:10.1007/s00401-015-1447-7

Cited by 62 publications

(67 citation statements)

References 83 publications

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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%

“…The current classification of sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, includes six major disease phenotypes that strongly correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine [M] or valine [V]) of the PRNP gene (which encodes PrP C ) and two PrP Sc profiles or types (type 1 and type 2) comprising distinctive physicochemical properties such as size after protease treatment (respectively, 21 and 19 kDa) and glycoform ratio (4,5). Recent studies in animal models have shown that phenotypic variations among sCJD phenotypes are largely maintained after transmission into genetically defined hosts, suggesting that different prion strains are the main cause of this diversity (6)(7)(8)(9)(10)(11). Although it is well established that PrP C conversion into PrP Sc involves consistent changes in the secondary structure with part of the ␣-helical structure turning into a ␤-sheet (12,13), a complete structural characterization of PrP Sc has been hampered by the propensity of the misfolded protein to form highly aggregated and detergent-insoluble polymers.…”

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confidence: 99%

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

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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%

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confidence: 99%

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

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et al. 2016

J Virol

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“…In sCJD patients, the methionine/valine (M/V) polymorphism at codon 129 of PRNP has a major influence on the susceptibility to and the progression of the disease [8][9][10]. Similar to sCJD, the clinicopathological phenotype in gCJD/fCJD may also depend on the M/V polymorphism at codon 129 of the mutated allele, e.g., in E200K carriers [11].…”

Section: Introductionmentioning

confidence: 98%

Hereditary Human Prion Diseases: an Update

et al. 2016

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Prion diseases in humans are neurodegenerative diseases which are caused by an accumulation of abnormal, misfolded cellular prion protein known as scrapie prion protein (PrP). Genetic, acquired, or spontaneous (sporadic) forms are known. Pathogenic mutations in the human prion protein gene (PRNP) have been identified in 10-15 % of CJD patients. These mutations may be single point mutations, STOP codon mutations, or insertions or deletions of octa-peptide repeats. Some non-coding mutations and new mutations in the PrP gene have been identified without clear evidence for their pathogenic significance. In the present review, we provide an updated overview of PRNP mutations, which have been documented in the literature until now, describe the change in the DNA, the family history, the pathogenicity, and the number of described cases, which has not been published in this complexity before. We also provide a description of each genetic prion disease type, present characteristic histopathological features, and the PrP isoform expression pattern of various familial/genetic prion diseases.

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“…In addition, polymorphic codon 129 of PRNP is partly associated with the risks of acquired prion diseases such as kuru, variant CJD, or iatrogenic CJD (Collinge et al 1991(Collinge et al , 1996, whereas polymorphic codon 127 and codon 219 are reportedly resistant to kuru (Mead et al 2009;Asante et al 2015) and sporadic CJD (Shibuya et al 1998), respectively. However, carrying these types of PRNP polymorphisms may not suggest whether a person will or will not develop the disease (Kobayashi et al 2015). Even carrying disease-linked PRNP mutations does not necessarily mean that a person will inevitably develop the disease.…”

Section: Preclinical Diagnosismentioning

confidence: 99%