Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils.
Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils.
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DOI：
10.1038/s41467-021-24362-8
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发表时间：
2021-07-09
影响因子：
16.6
通讯作者：
Zweckstetter M
中科院分区：
文献类型：
--
作者：
Chakraborty P;Rivière G;Liu S;de Opakua AI;Dervişoğlu R;Hebestreit A;Andreas LB;Vorberg IM;Zweckstetter M
tau蛋白病理聚集成不溶性聚集体是神经退行性疾病的标志。然而，被称为tau菌株的疾病特异性tau聚集结构的出现仍然难以捉摸。在这里，我们表明全长tau蛋白可以在没有辅助因子的情况下聚集成能够隔离RNA的具有播种能力的淀粉样蛋白原纤维。利用固态核磁共振波谱和生化实验的结合，我们证明了tau蛋白的无辅助因子淀粉样原纤维具有刚性核，其大小和位置与从皮质基底变性患者的大脑中纯化的tau蛋白原纤维的刚性核相似。此外，我们证明tau蛋白的n -末端30残基在纤维形成过程中被固定，这与病理tau蛋白中抗体特异性检测到的n -末端表位的存在一致。体外和生物传感器细胞实验进一步证实，无辅助因子的tau原纤维能有效地促进tau聚集，而与不同RNA的结合研究表明，无辅助因子的tau原纤维能强烈地隔离RNA。综上所述，该研究为揭示引导疾病特异性tau菌株聚集的分子因素提供了重要进展。作者提出了一种不需要肝素或其他带负电荷的辅助因子就能将全长tau蛋白转化为具有播种能力的淀粉样蛋白原纤维的方法，这可能有助于研究翻译后修饰对tau聚集的影响，以及识别tau聚集的潜在抑制剂。生化实验和固态核磁共振光谱测量表明，这些无辅助因子的tau蛋白原纤维与从脑组织中分离的淀粉样蛋白原纤维具有相似的特性，但与常用的肝素诱导的tau蛋白原纤维不同。
Pathological aggregation of the protein tau into insoluble aggregates is a hallmark of neurodegenerative diseases. The emergence of disease-specific tau aggregate structures termed tau strains, however, remains elusive. Here we show that full-length tau protein can be aggregated in the absence of co-factors into seeding-competent amyloid fibrils that sequester RNA. Using a combination of solid-state NMR spectroscopy and biochemical experiments we demonstrate that the co-factor-free amyloid fibrils of tau have a rigid core that is similar in size and location to the rigid core of tau fibrils purified from the brain of patients with corticobasal degeneration. In addition, we demonstrate that the N-terminal 30 residues of tau are immobilized during fibril formation, in agreement with the presence of an N-terminal epitope that is specifically detected by antibodies in pathological tau. Experiments in vitro and in biosensor cells further established that co-factor-free tau fibrils efficiently seed tau aggregation, while binding studies with different RNAs show that the co-factor-free tau fibrils strongly sequester RNA. Taken together the study provides a critical advance to reveal the molecular factors that guide aggregation towards disease-specific tau strains. The authors present a method for the conversion of full-length tau protein into seeding-competent amyloid fibrils without heparin or other negatively charged co-factors, which could be useful for studying the effects of post-translational modifications on Tau aggregation as well as to identify potential inhibitors of tau aggregation. Biochemical experiments and solid-state NMR spectroscopy measurements show that these co-factor-free tau fibrils have similar properties as amyloid fibrils isolated from brain tissue but differ from those of commonly used heparin-induced tau fibrils.
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影响因子：
15
作者：
Daebel, Venita;Chinnathambi, Subashchandrabose;Lange, Adam
通讯作者：
Lange, Adam
影响因子：
2.9
作者：
Vranken, WF;Boucher, W;Laue, ED
通讯作者：
Laue, ED
DOI：
10.1073/pnas.1906839116
发表时间：
2019-08-13
影响因子：
11.1
作者：
Dregni, Aurelio J.;Mandala, Venkata S.;Hong, Mei
通讯作者：
Hong, Mei
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE
使用三苯甲基氮氧双自由基在 800 MHz/527 GHz 下实现高效动态核极化。
DOI：
10.1002/anie.201504292
发表时间：
2015-09-28
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Mathies G;Caporini MA;Michaelis VK;Liu Y;Hu KN;Mance D;Zweier JL;Rosay M;Baldus M;Griffin RG
通讯作者：
Griffin RG