Down-regulation of Shadoo in prion infections traces a pre-clinical event inversely related to PrP(Sc) accumulation.
Down-regulation of Shadoo in prion infections traces a pre-clinical event inversely related to PrP(Sc) accumulation.
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DOI：
10.1371/journal.ppat.1002391
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发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Carlson GA
中科院分区：
文献类型：
--
作者：
Westaway D;Genovesi S;Daude N;Brown R;Lau A;Lee I;Mays CE;Coomaraswamy J;Canine B;Pitstick R;Herbst A;Yang J;Ko KW;Schmitt-Ulms G;Dearmond SJ;McKenzie D;Hood L;Carlson GA
在Prion感染中枢神经系统(CNS)的过程中，细胞内的Prion蛋白PrPc被模板化为构象不同的形式PrPSc。最近的研究表明，Sprn基因编码一种GPI连接的糖蛋白Shadoo(Sho)，它定位于与PrPC相似的膜环境中，并在终末期Prion病啮齿类动物的脑组织中被还原。在这里，对感染普恩病毒的小鼠的分析表明，在普恩病毒感染的任何阶段，Sho蛋白的下调与Sprn mRNA的丰度无关。在PRNP a和PRNP b小鼠中，除了小鼠适应的BSE菌株301 V外，在各种Pron菌株的繁殖过程中，下调都很强烈。此外，TgSprn转基因编码的Sho的下调程度与内源性Sho的下调程度相同。在牛磺酸病、化学诱导的海绵状变性或表达丹麦家族性痴呆的细胞外Adan淀粉样多肽的转基因小鼠中，ShO水平未见降低。如果感染PrNP的PrNP半合子小鼠在神经系统症状出现前数百天就表现出PrPSc的积聚和Sho的下调，Sho的耗竭可以被排除为临床疾病的重要触发因素或神经元损伤的简单后果。相反，这些研究定义了一种疾病特异性效应，我们假设与膜相关的ShO包括降解PrPSc过程的旁观者底物。因此，虽然通过体外消化检测到的具有蛋白酶抗性的PrP可以进行死后诊断，但内源性Sho水平的降低可能是对体内CNS中PrPSc积累的早期反应。这种细胞反应可能为检测和清除错误折叠的蛋白质提供了新的见解，这些机制涉及到检测和清除错误折叠的蛋白质，这些蛋白质驱动了Pron病的发病机制。在神经系统的Prion感染中，细胞内的Prion蛋白PrPc会转变为一种不同的形式PrPSc。最近的研究表明，另一种糖蛋白Shadoo(Sho)与PrPC处于相似的膜环境，在终末期PrP病啮齿类动物的大脑中被还原。我们对感染Prion的小鼠的分析表明，Sho蛋白的减少并不是由于相应的信使RNA减少所致。在繁殖各种普恩病毒株时，ShO的减少是明显的，但在患有其他类型的神经退行性疾病的小鼠中却看不到。此外，由于只有一个PrP基因拷贝的普恩病毒感染小鼠在神经系统症状出现前数百天就表现出PrPSc的积累和Sho蛋白的减少，Sho蛋白水平的下降可以被排除为临床疾病的重要触发因素，或脑细胞损伤的非特异性后果。相反，我们的研究定义了一种仅限于PrPSc疾病的效应，并假设Sho蛋白是旨在摧毁PrPSc的降解过程的“旁观者”。
During prion infections of the central nervous system (CNS) the cellular prion protein, PrPC, is templated to a conformationally distinct form, PrPSc. Recent studies have demonstrated that the Sprn gene encodes a GPI-linked glycoprotein Shadoo (Sho), which localizes to a similar membrane environment as PrPC and is reduced in the brains of rodents with terminal prion disease. Here, analyses of prion-infected mice revealed that down-regulation of Sho protein was not related to Sprn mRNA abundance at any stage in prion infection. Down-regulation was robust upon propagation of a variety of prion strains in Prnp a and Prnp b mice, with the exception of the mouse-adapted BSE strain 301 V. In addition, Sho encoded by a TgSprn transgene was down-regulated to the same extent as endogenous Sho. Reduced Sho levels were not seen in a tauopathy, in chemically induced spongiform degeneration or in transgenic mice expressing the extracellular ADan amyloid peptide of familial Danish dementia. Insofar as prion-infected Prnp hemizygous mice exhibited accumulation of PrPSc and down-regulation of Sho hundreds of days prior to onset of neurologic symptoms, Sho depletion can be excluded as an important trigger for clinical disease or as a simple consequence of neuronal damage. These studies instead define a disease-specific effect, and we hypothesize that membrane-associated Sho comprises a bystander substrate for processes degrading PrPSc. Thus, while protease-resistant PrP detected by in vitro digestion allows post mortem diagnosis, decreased levels of endogenous Sho may trace an early response to PrPSc accumulation that operates in the CNS in vivo. This cellular response may offer new insights into the homeostatic mechanisms involved in detection and clearance of the misfolded proteins that drive prion disease pathogenesis. In prion infections of the nervous system the cellular prion protein, PrPC, changes to a distinct form, PrPSc. Recent studies have demonstrated that another glycoprotein Shadoo (Sho), which occupies a similar membrane environment as PrPC, is reduced in the brains of rodents with terminal prion disease. Our analyses of prion-infected mice revealed that reduction of Sho protein was not due to reductions in the corresponding messenger RNA. Reduction in Sho was clearly evident upon propagation of a variety of prion strains, but was not seen in mice with other types of neurodegenerative disease. Also, as prion-infected mice with only one copy of the PrP gene exhibited both accumulation of PrPSc and a reduction of Sho protein hundreds of days prior to onset of neurologic symptoms, the drop in Sho protein level can be excluded as an important trigger for clinical disease, or a non-specific consequence of brain cell damage. Instead, our studies define a effect restricted to prion disease and we hypothesize that Sho protein is a “bystander” for degradative processes aimed at destroying PrPSc.
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