The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease.
The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease.
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prion蛋白蛋白质蛋白酶敏感性，稳定性和播种活性在可变的蛋白酶敏感的prionopathy脑组织中表明分子与零星的creutzfeldt-jakob疾病重叠。
DOI：
10.1186/s40478-014-0152-4
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发表时间：
2014-10-21
影响因子：
7.1
通讯作者：
Head MW
中科院分区：
文献类型：
--
作者：
Peden AH;Sarode DP;Mulholland CR;Barria MA;Ritchie DL;Ironside JW;Head MW
可变蛋白酶敏感性朊病毒病（VPSPr）是最近描述的散发性人类朊病毒病，其在病理学和生物化学上不同于目前公认的散发性克雅氏病（sCJD）亚型。VPSPr中朊病毒蛋白（PrPSc）异常形式的定义生化特征是对蛋白水解的敏感性增加以及存在N-和C-末端切割的~8 kDa蛋白酶抗性PrPSc（PrPres）片段。VPSPr的生物化学和神经病理学特征被认为类似于Gerstmann-Sträussler-Scheinker综合征（GSS）或家族性CJD（PRNP-V180 I突变）。然而，在VPSPr的某些情况下，在蛋白质印迹中观察到两条蛋白酶抗性条带，它们与2型PrPres的条带共迁移，这表明VPSPr中存在的PrPSc的比例与sCJD的性质相似。在这里，我们已经使用构象依赖性免疫测定来确认VPSPr中PrPSc的存在，其与sCJD相比更蛋白酶敏感。然而，CDI还显示VPSPr中的一部分PrPSc抵抗其C-末端的PK消化，将其与与约8 kDa PrPres相关的GSS区分开来，并显示与sCJD的相似性。对单个VPSPr病例（冷冻组织来自多个脑区）的深入研究显示，在不存在PK治疗的情况下，PrPSc具有广泛的区域特异性蛋白酶敏感性谱和差异稳定性。最后，使用蛋白质错误折叠循环扩增和实时震动诱导转化，我们表明VPSPr PrPSc具有体外种子转化的潜力，并且种子活性分散在广泛的聚集体尺寸范围内。我们进一步提出，接种活性与~19和~23 kDa的PrPres，而不是~8 kDa的片段。因此，VPSPr中的PrPSc在蛋白酶敏感性和对离液剂GdnHCl变性的稳定性方面是异质的，并且包括与在sCJD中发现的性质相似的比例。本文的在线版本（doi：10.1186/s40478-014-0152-4）包含补充材料，可供授权用户使用。
Variably protease sensitive prionopathy (VPSPr) is a recently described, sporadic human prion disease that is pathologically and biochemically distinct from the currently recognised sporadic Creutzfeldt-Jakob disease (sCJD) subtypes. The defining biochemical features of the abnormal form of the prion protein (PrPSc) in VPSPr are increased sensitivity to proteolysis and the presence of an N- and C-terminally cleaved ~8 kDa protease resistant PrPSc (PrPres) fragment. The biochemical and neuropathological profile of VPSPr has been proposed to resemble either Gerstmann–Sträussler–Scheinker syndrome (GSS) or familial CJD with the PRNP-V180I mutation. However, in some cases of VPSPr two protease resistant bands have been observed in Western blots that co-migrate with those of type 2 PrPres, suggesting that a proportion of the PrPSc present in VPSPr has properties similar to those of sCJD. Here, we have used conformation dependent immunoassay to confirm the presence of PrPSc in VPSPr that is more protease sensitive compared with sCJD. However, CDI also shows that a proportion of PrPSc in VPSPr resists PK digestion of its C-terminus, distinguishing it from GSS associated with ~8 kDa PrPres, and showing similarity to sCJD. Intensive investigation of a single VPSPr case with frozen tissue from multiple brain regions shows a broad, region-specific spectrum of protease sensitivity and differential stability of PrPSc in the absence of PK treatment. Finally, using protein misfolding cyclic amplification and real-time quaking induced conversion, we show that VPSPr PrPSc has the potential to seed conversion in vitro and that seeding activity is dispersed through a broad range of aggregate sizes. We further propose that seeding activity is associated with the ~19 and ~23 kDa PrPres rather than the ~8 kDa fragment. Therefore, PrPSc in VPSPr is heterogeneous in terms of protease sensitivity and stability to denaturation with the chaotrope GdnHCl and includes a proportion with similar properties to that found in sCJD. The online version of this article (doi:10.1186/s40478-014-0152-4) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Xiao X;Yuan J;Haïk S;Cali I;Zhan Y;Moudjou M;Li B;Laplanche JL;Laude H;Langeveld J;Gambetti P;Kitamoto T;Kong Q;Brandel JP;Cobb BA;Petersen RB;Zou WQ
通讯作者：
Zou WQ
影响因子：
3.8
作者：
Choi, Young Pyo;Groener, Albrecht;Head, Mark W.
通讯作者：
Head, Mark W.
影响因子：
5.4
作者：
Choi, Young Pyo;Peden, Alexander H.;Head, Mark W.
通讯作者：
Head, Mark W.
DOI：
10.1097/00005072-199810000-00010
发表时间：
1998-10-01
影响因子：
3.2
作者：
Piccardo, P;Dlouhy, SR;Ghetti, B
通讯作者：
Ghetti, B
影响因子：
14.5
作者：
Cali, Ignazio;Castellani, Rudolph;Gambetti, Pierluigi
通讯作者：
Gambetti, Pierluigi