Structural disorder in four-repeat Tau fibrils reveals a new mechanism for barriers to cross-seeding of Tau isoforms
Structural disorder in four-repeat Tau fibrils reveals a new mechanism for barriers to cross-seeding of Tau isoforms
复制标题
四重复 Tau 原纤维的结构紊乱揭示了阻碍 Tau 亚型交叉播种的新机制
DOI：
10.1074/jbc.ra118.005316
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发表时间：
2018-11-09
影响因子：
4.8
通讯作者：
Margittai, Martin
中科院分区：
文献类型：
--
作者：
Weismiller, Hilary A.;Murphy, Rachel;Margittai, Martin
由微管相关蛋白Tau组成的原纤维的细胞内沉积是阿尔茨海默病（AD）和统称为Tau病的其他致命神经退行性疾病的特征性特征。短Tau纤维通过相互连接的神经元之间的转移在脑内扩散。一旦被受体细胞吸收，Tau原纤维将Tau单体募集到其末端。基于微管结合重复序列的数量，存在两组不同的Tau同种型：三重复（3R）Tau和四重复（4R）Tau。在AD中，所有Tau同种型都沉积，而在其他Tau病中，仅3R或4R Tau同种型沉积。这些异构体特异性沉积的分子基础知之甚少，尽管基于构象的交叉接种障碍是关键。在这里，我们使用沉降测定、EPR光谱和其他结构读数来更好地理解4R Tau原纤维的交叉接种屏障。我们观察到由截短的Tau（K18）而非全长Tau（htau40）形成的原纤维表现出抑制3R Tau募集的屏障。研究一系列不同大小的片段，我们发现Tau C末端调节交叉接种屏障，N末端起协同作用。两种疾病相关的Tau变体P301S和P301L也建立了强大的交叉接种屏障。EPR分析表明，接种有截短和突变的Tau，但不是htau40的原纤维在第四个重复序列的后半部分及以后是结构无序的。这些发现表明，该区域的紊乱降低了4R Tau原纤维募集3R Tau单体的能力，揭示了Tau交叉接种屏障的新机制。
The intracellular deposition of fibrils composed of the microtubule-associated protein Tau is a characteristic feature of Alzheimer's disease (AD) and other fatal neurodegenerative disorders collectively known as tauopathies. Short Tau fibrils spread intracerebrally through transfer between interconnected neurons. Once taken up by a recipient cell, Tau fibrils recruit Tau monomers onto their ends. Based on the number of microtubule-binding repeats, there are two distinct groups of Tau isoforms: three-repeat (3R) Tau and four-repeat (4R) Tau. In AD, all Tau isoforms are deposited, whereas in other tauopathies, only 3R or 4R Tau isoforms are deposited. The molecular basis for these isoform-specific depositions is poorly understood, although conformation-based cross-seeding barriers are key. Here, we used sedimentation assays, EPR spectroscopy, and other structural readouts to better understand the cross-seeding barriers of 4R Tau fibrils. We observed that fibrils formed from truncated Tau (K18), but not full-length Tau (htau40), exhibit a barrier that inhibits 3R Tau recruitment. Investigating an array of differently sized fragments, we found that the Tau C terminus modulates the cross-seeding barrier and that the N terminus plays a synergistic role. Two disease-associated Tau variants, P301S and P301L, also established strong cross-seeding barriers. EPR analysis indicated that fibrils seeded with truncated and mutated Tau, but not htau40, are structurally disordered in the second half of repeat four and onward. These findings suggest that the disorder in this region diminishes the ability of 4R Tau fibrils to recruit 3R Tau monomers, revealing a new mechanism for Tau cross-seeding barriers.