Conformation determines the seeding potencies of native and recombinant Tau aggregates.
Conformation determines the seeding potencies of native and recombinant Tau aggregates.
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DOI：
10.1074/jbc.m114.589309
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发表时间：
2015-01-09
期刊：
影响因子：
--
通讯作者：
Bose S
中科院分区：
文献类型：
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作者：
Falcon B;Cavallini A;Angers R;Glover S;Murray TK;Barnham L;Jackson S;O'Neill MJ;Isaacs AM;Hutton ML;Szekeres PG;Goedert M;Bose S
背景：种子感受态Tau的特征未知。结果：天然Tau聚集体具有比重组Tau聚集体更高的接种效力。重组Tau通过接种组装获得天然Tau聚集体的构象和效力。结论：构象决定Tau聚集体的接种效力。意义：了解种子感受态Tau的特性可以深入了解疾病机制。细胞内Tau包涵体是几种神经退行性疾病的病理学标志，统称为Tau病变。它们包括阿尔茨海默病、缠结性痴呆、皮克病、嗜银颗粒病、慢性创伤性脑病、进行性核上性麻痹和皮质基底节变性。Tau病理似乎通过细胞间传播传播，需要形成组装的“朊病毒样”物质。已经描述了几种细胞和动物模型，概括了这种现象的各个方面。然而，种子感受态Tau的分子特征仍不清楚。在这里，我们已经使用细胞模型来理解Tau结构/磷酸化与来自人突变型P301 S Tau和全长聚集重组P301 S Tau转基因小鼠脑的聚集Tau种类的接种之间的关系。基序275 VQIINK 280和306 VQIVYK 311的缺失消除了重组全长Tau的接种活性，表明其聚集是接种所必需的。我们描述了天然和合成的Tau聚集体之间的构象差异，这可能是天然组装的Tau的更高接种活性的原因。当添加到来自P301 S Tau转基因小鼠脑的聚集Tau种子中时，可溶性重组Tau聚集并获得来自转基因小鼠脑的聚集Tau的分子性质。我们表明，播种是由聚集的Tau赋予的，Tau通过巨胞饮作用进入细胞，并将内源性Tau的组装播种成细丝。
Background: Characteristics of seed-competent Tau are unknown. Results: Native Tau aggregates have a higher seeding potency than recombinant Tau aggregates. Recombinant Tau acquires the conformation and potency of native Tau aggregates by seeded assembly. Conclusion: Conformation determines the seeding potencies of Tau aggregates. Significance: Understanding the properties of seed-competent Tau gives insight into disease mechanisms. Intracellular Tau inclusions are a pathological hallmark of several neurodegenerative diseases, collectively known as the tauopathies. They include Alzheimer disease, tangle-only dementia, Pick disease, argyrophilic grain disease, chronic traumatic encephalopathy, progressive supranuclear palsy, and corticobasal degeneration. Tau pathology appears to spread through intercellular propagation, requiring the formation of assembled “prion-like” species. Several cell and animal models have been described that recapitulate aspects of this phenomenon. However, the molecular characteristics of seed-competent Tau remain unclear. Here, we have used a cell model to understand the relationships between Tau structure/phosphorylation and seeding by aggregated Tau species from the brains of mice transgenic for human mutant P301S Tau and full-length aggregated recombinant P301S Tau. Deletion of motifs 275VQIINK280 and 306VQIVYK311 abolished the seeding activity of recombinant full-length Tau, suggesting that its aggregation was necessary for seeding. We describe conformational differences between native and synthetic Tau aggregates that may account for the higher seeding activity of native assembled Tau. When added to aggregated Tau seeds from the brains of mice transgenic for P301S Tau, soluble recombinant Tau aggregated and acquired the molecular properties of aggregated Tau from transgenic mouse brain. We show that seeding is conferred by aggregated Tau that enters cells through macropinocytosis and seeds the assembly of endogenous Tau into filaments.