Tau mutation S356T in the three repeat isoform leads to microtubule dysfunction and promotes prion-like seeded aggregation.
Tau mutation S356T in the three repeat isoform leads to microtubule dysfunction and promotes prion-like seeded aggregation.
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DOI：
10.3389/fnins.2023.1181804
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发表时间：
2023
影响因子：
4.3
通讯作者：
Giasson, Benoit I. I.
中科院分区：
文献类型：
--
作者：
Xia, Yuxing;Bell, Brach M. M.;Kim, Justin D. D.;Giasson, Benoit I. I.
Tau病是一组神经退行性疾病，包括额颞叶痴呆(FTD)和阿尔茨海默病(AD)，广义上定义为tau脑团聚体的发育。Tau错义突变和剪接突变均可直接导致早发性FTD。Tau蛋白是一种微管相关蛋白，可以稳定和调节微管，但这一功能在疾病状态下可能会被破坏。一个促成因素是不同tau亚型的平衡，根据表达的微管结合重复序列的数量，可以将其分为三个重复(3R)或四个重复(4R)亚型。3R和4R亚型在两个方向上的不平衡都会导致FTD和神经变性。也有越来越多的证据表明，3R tauopathy，如Pick病，形成tau聚集体，主要由3R亚型组成，这些亚型可以表现出不同于4R和混合3R/4R tauopathy。在这项研究中，我们评估了3R tau基因的多个突变的MT结合特性和类Pron聚集倾向。不同的tau错义突变对MT结合的影响因分子位置和性质而异。在所调查的突变中，S356T tau是唯一能够形成类似于Pron的种子聚集并形成广泛的硫代黄素阳性聚集体的突变。这种独特的蛋白样tau株将有助于模拟3R tau聚集，并有助于理解不同tauopathy的不同表现形式。
Tauopathies are a group of neurodegenerative diseases, which include frontotemporal dementia (FTD) and Alzheimer’s disease (AD), broadly defined by the development of tau brain aggregates. Both missense and splicing tau mutations can directly cause early onset FTD. Tau protein is a microtubule-associated protein that stabilizes and regulates microtubules, but this function can be disrupted in disease states. One contributing factor is the balance of different tau isoforms, which can be categorized into either three repeat (3R) or four repeat (4R) isoforms based on the number of microtubule-binding repeats that are expressed. Imbalance of 3R and 4R isoforms in either direction can cause FTD and neurodegeneration. There is also increasing evidence that 3R tauopathies such as Pick’s disease form tau aggregates predominantly comprised of 3R isoforms and these can present differently from 4R and mixed 3R/4R tauopathies. In this study, multiple mutations in 3R tau were assessed for MT binding properties and prion-like aggregation propensity. Different missense tau mutations showed varying effects on MT binding depending on molecular location and properties. Of the mutations that were surveyed, S356T tau is uniquely capable of prion-like seeded aggregation and forms extensive Thioflavin positive aggregates. This unique prion-like tau strain will be useful to model 3R tau aggregation and will contribute to the understanding of diverse presentations of different tauopathies.
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