Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures.

来自散发性 Creutzfeldt-Jakob 病患者的朊病毒作为菌株混合物繁殖。

  • 影响因子:6.74700
  • DOI:10.1128/mBio.00393-20
  • 作者列表:"Cassard H","Huor A","Espinosa JC","Douet JY","Lugan S","Aron N","Vilette D","Delisle MB","Marín-Moreno A","Peran P","Beringue V","Torres JM","Ironside JW","Andreoletti O
  • 发表时间:2020-06-16

:Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrPres) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrPres were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates (n = 29) that displayed either a single or mixed type 1/type 2 PrPres were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1CJD and V2CJD) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1CJD and V2CJD strains, including in patients who displayed a "pure" type 1 or type 2 PrPres The use of a highly sensitive prion in vitro amplification technique that specifically probes the V2CJD strain revealed the presence of the V2CJD prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1CJD strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient.IMPORTANCE sCJD occurrence is currently assumed to result from spontaneous and stochastic formation of a misfolded PrP nucleus in the brains of affected patients. This original nucleus then recruits and converts nascent PrPC into PrPSc, leading to the propagation of prions in the patient's brain. Our study demonstrates the coexistence of two prion strains in the brains of a majority of the 23 sCJD patients investigated. The relative proportion of these sCJD strains varied both between patients and between brain areas in a single patient. These findings strongly support the view that the replication of an sCJD prion strain in the brain of a patient can result in the propagation of different prion strain subpopulations. Beyond its conceptual importance for our understanding of prion strain properties and evolution, the sCJD strain mixture phenomenon and its frequency among patients have important implications for the development of therapeutic strategies for prion diseases.


: 散发性 Creutzfeldt-Jakob 病 (sCJD) 病例目前根据 PRNP 基因 129 密码子的蛋氨酸/缬氨酸多态性和蛋白酶 K 消化的异常朊蛋白 (PrPres) 进行分类 western blotting 鉴定的亚型 (1 型或 2 型)。会聚证据导致认为 MM/MV1 、 VV/MV2 和 VV1 和 MM2 sCJD 病例是由不同的朊病毒菌株引起的。然而,在相当大比例的 sCJD 患者中,报告 1 型和 2 型 PrPres 都在大脑中蓄积,这就对 sCJD 朊病毒菌株的多样性以及同一患者体内两种朊病毒菌株的共存提出了疑问。在这项研究中,一组 sCJD 脑分离株 (n = 29) 显示单一或混合型 1/2 型 PrPres 被传递到表达人 PrP 的小鼠 (tgHu) 中。这些生物测定证明,两种不同的朊病毒菌株 (M1CJD 和 V2CJD) 与 MM1/MV1 和 VV2/MV2 患者 sCJD 的发生相关。然而,在大约 35% 的研究 VV 和 MV 病例中,传播结果与 M1CJD 和 V2CJD 菌株的存在一致,包括在显示 “纯” 的患者中1 型或 2 型 PrPres 使用高度敏感的朊病毒体外扩增技术,特异性检测 V2CJD 菌株,发现超过 80% 的研究分离株存在 V2CJD 朊病毒,包括在 thu 中作为纯 M1CJD 菌株繁殖的分离株。这些结果表明,在单个患者中至少可以存在两个 sCJD 朊病毒菌株。重要性 sCJD 的发生目前被认为是受累患者大脑中自发和随机形成错误折叠的 PrP 核的结果。这个原始细胞核然后招募并将新生的 PrPC 转化为 PrPSc,导致朊病毒在患者大脑中的传播。我们的研究证明了在研究的 23 例 sCJD 患者中,大多数患者的大脑中存在两种朊病毒菌株的共存。这些 sCJD 菌株的相对比例在患者之间和单个患者的脑区之间都存在差异。这些发现强烈支持这样的观点,即 sCJD 朊病毒菌株在患者大脑中的复制可以导致不同朊病毒菌株亚群的繁殖。除了对我们理解朊病毒菌株特性和进化的概念重要性之外,sCJD 菌株混合现象及其在患者中的频率对发展朊病毒疾病的治疗策略具有重要意义。



作者列表:["Maddox RA","Person MK","Blevins JE","Abrams JY","Appleby BS","Schonberger LB","Belay ED"]

METHODS:OBJECTIVE:To report the incidence of prion disease in the United States. METHODS:Prion disease decedents were retrospectively identified from the US national multiple cause-of-death data for 2003-2015 and matched with decedents in the National Prion Disease Pathology Surveillance Center (NPDPSC) database through comparison of demographic variables. NPDPSC decedents with neuropathologic or genetic test results positive for prion disease for whom no match was found in the multiple cause-of-death data were added as cases for incidence calculations; those with cause-of-death data indicating prion disease but with negative neuropathology results were removed. Age-specific and age-adjusted average annual incidence rates were then calculated. RESULTS:A total of 5,212 decedents were identified as having prion disease, for an age-adjusted average annual incidence of 1.2 cases per million population (range 1.0 per million [2004 and 2006] to 1.4 per million [2013]). The median age at death was 67 years. Ten decedents were <30 years of age (average annual incidence of 6.2 per billion); only 2 of these very young cases were sporadic forms of prion disease. Average annual incidence among those ≥65 years of age was 5.9 per million. CONCLUSIONS:Prion disease incidence can be estimated by augmenting mortality data with the results of neuropathologic and genetic testing. Cases <30 years of age were extremely rare, and most could be attributed to exogenous factors or the presence of a genetic mutation. Continued vigilance for prion diseases in all age groups remains prudent.

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作者列表:["Soto P","Claflin IA","Bursott AL","Schwab-McCoy AD","Bartz JC"]

METHODS::The conformational conversion of the cellular prion protein (PrPC) to the misfolded and aggregated isoform, termed scrapie prion protein (PrPSc), is key to the development of a group of neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). Although the conversion mechanism is not fully understood, the role of gene polymorphisms in varying susceptibilities to prion diseases is well established. In ovine, specific gene polymorphisms in PrPC alter prion disease susceptibility: the Valine136-Glutamine171 variant (Susceptible structure) displays high susceptibility to classical scrapie while the Alanine136-Arginine171 variant (Resistant structure) displays reduced susceptibility. The opposite trend has been reported in atypical scrapie. Despite the differentiation between classical and atypical scrapie, a complete understanding of the effect of polymorphisms on the structural dynamics of PrPC is lacking. From our structural bioinformatics study, we propose that polymorphisms locally modulate the network of residue interactions in the globular C-terminus of the ovine recombinant prion protein while maintaining the overall fold. Although the two variants we examined exhibit a densely connected group of residues that includes both β-sheets, the β2-α2 loop and the N-terminus of α-helix 2, only in the Resistant structure do most residues of α-helix 2 belong to this group. We identify the structural role of Valine136Alanine and Glutamine171Arginine: modulation of residue interaction networks that affect the connectivity between α-helix 2 and α-helix 3. We propose blocking interactions of residue 171 as a potential target for the design of therapeutics to prevent efficient PrPC misfolding. We discuss our results in the context of initial PrPC conversion and extrapolate to recently proposed PrPSc structures.Communicated by Ramaswamy H. Sarma.

作者列表:["Espinosa JC","Marín-Moreno A","Aguilar-Calvo P","Benestad SL","Andreoletti O","Torres JM"]

METHODS::Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]-Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.

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