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Quaternary Structure Changes for PrPSc Predate PrPC Downregulation and Neuronal Death During Progression of Experimental Scrapie Disease.
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2020-09-21 , DOI: 10.1007/s12035-020-02112-z
Ghazaleh Eskandari-Sedighi 1, 2 , Leonardo M Cortez 2, 3 , Jing Yang 2 , Nathalie Daude 2 , Klinton Shmeit 2 , Valerie Sim 2, 3 , David Westaway 1, 2
Affiliation  

Prion diseases are fatal neurodegenerative diseases in mammals with the unique characteristics of misfolding and aggregation of the cellular prion protein (PrPC) to the scrapie prion (PrPSc). Although neuroinflammation and neuronal loss feature within the disease process, the details of PrPC/PrPSc molecular transition to generate different aggregated species, and the correlation between each species and sequence of cellular events in disease pathogenesis are not fully understood. In this study, using mice inoculated with the RML isolate of mouse-adapted scrapie as a model, we applied asymmetric flow field-flow fractionation to monitor PrPC and PrPSc particle sizes and we also measured seeding activity and resistance to proteases. For cellular analysis in brain tissue, we measured inflammatory markers and synaptic damage, and used the isotropic fractionator to measure neuronal loss; these techniques were applied at different timepoints in a cross-sectional study of disease progression. Our analyses align with previous reports defining significant decreases in PrPC levels at pre-clinical stages of the disease and demonstrate that these decreases become significant before neuronal loss. We also identified the earliest PrPSc assemblies at a timepoint equivalent to 40% elapsed time for the disease incubation period; we propose that these assemblies, mostly composed of proteinase K (PK)–sensitive species, play an important role in triggering disease pathogenesis. Lastly, we show that the PK-resistant assemblies of PrPSc that appear at timepoints close to the terminal stage have similar biophysical characteristics, and hence that preparative use of PK-digestion selects for this specific subpopulation. In sum, our data argue that qualitative, as well as quantitative, changes in PrP conformers occur at the midpoint of subclinical phase; these changes affect quaternary structure and may occur at the threshold where adaptive responses become inadequate to deal with pathogenic processes.



中文翻译:

PrPSc 的四级结构变化早于 PrPC 下调和实验性痒病进展期间的神经元死亡。

朊病毒病是与错折叠和蜂窝朊病毒蛋白(PrP蛋白聚集的独特特性哺乳动物致命的神经变性疾病Ç)与瘙痒病朊病毒(PrP的)。虽然神经炎症和神经元丢失在疾病过程中具有特征,但 PrP C / PrP Sc分子转变以产生不同聚集物种的细节,以及每个物种与疾病发病机制中细胞事件序列之间的相关性尚不完全清楚。在这项研究中,使用接种了小鼠适应痒病 RML 分离株的小鼠作为模型,我们应用非对称流场-流动分级来监测 PrP C和 PrP Sc颗粒大小,我们还测量了接种活性和蛋白酶抗性。对于脑组织的细胞分析,我们测量了炎症标志物和突触损伤,并使用各向同性分馏器测量神经元损失;这些技术在不同时间点应用于疾病进展的横断面研究。我们的分析与以前的报告中定义的PrP显著下跌对准Ç在疾病的临床前阶段的水平,并证明这些减少成为神经元丢失之前显著。我们还确定了最早的 PrP Sc在相当于疾病潜伏期 40% 的时间点组装;我们认为这些组装体主要由蛋白酶 K (PK) 敏感物种组成,在触发疾病发病机制中发挥重要作用。最后,我们表明在接近终末阶段的时间点出现的 PrP Sc的 PK 抗性组件具有相似的生物物理特征,因此准备使用 PK 消化选择该特定亚群。总之,我们的数据表明,PrP 构象异构体的定性和定量变化发生在亚临床阶段的中点;这些变化会影响四级结构,并且可能发生在适应性反应不足以应对致病过程的阈值处。

更新日期:2020-11-27
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