Variations in Filament Conformation Dictate Seeding Barrier between Three- and Four-Repeat Tau
Variations in Filament Conformation Dictate Seeding Barrier between Three- and Four-Repeat Tau
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DOI：
10.1021/bi2004685
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发表时间：
2011-05-24
期刊：
影响因子：
2.9
通讯作者：
Margittai, Martin
中科院分区：
文献类型：
--
作者：
Dinkel, Paul D.;Siddiqua, Ayisha;Margittai, Martin
Tau丝是>20种神经退行性疾病（包括阿尔茨海默病）的病理学标志。存在六种tau同种型，其可基于四种微管结合重复序列中的第二种的存在或不存在而分为4-重复序列（4 R）tau和3-重复序列（3R）tau。最近的证据表明，tau蛋白丝可以在细胞之间转移并在大脑中扩散。在这里，我们证明了在体外，种子丝的生长，一个先决条件的tau扩散，是至关重要的依赖于异构体组成的个别种子。3R tau和3R/4 R tau的种子募集两种类型的同种型。4 R tau的种子募集4 R tau，但不募集3R tau，从而建立不对称屏障。将4 R tau构象模板化到3R tau种子上消除了这种障碍，产生了一种新型的tau丝。这些发现为tau细丝的播种、繁殖和多样化提供了基本的机制见解。
Tau filaments are the pathological hallmark of >20 neurodegenerative diseases including Alzheimer's disease. Six tau isoforms exist that can be grouped into 4-repeat (4R) tau and 3-repeat (3R) tau based on the presence or absence of the second of four microtubule binding repeats. Recent evidence suggests that tau filaments can transfer between cells and spread through the brain. Here we demonstrate in vitro that seeded filament growth, a prerequisite for tau spreading, is crucially dependent on the isoform composition of individual seeds. Seeds of 3R tau and 3R/4R tau recruit both types of isoforms. Seeds of 4R tau recruit 4R tau, but not 3R tau, establishing an asymmetric barrier. Conformational templating of 4R tau onto 3R tau seeds eliminates this barrier, giving rise to a new type of tau filament. These findings provide fundamental mechanistic insights into the seeding, propagation, and diversification of tau filaments.