<br>疾病相关的 Tau 编码突变导致聚集结构构象变化,ACS Chemical Neuroscience

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疾病相关的 Tau 编码突变导致聚集结构构象变化
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2023-12-06 , DOI: 10.1021/acschemneuro.3c00422
Kerry T Sun ₁ , Tark Patel ₁ , Sang-Gyun Kang ₁ , Allan Yarahmady ₁ , Mahalashmi Srinivasan ₁ , Olivier Julien ₁ , Jónathan Heras ₂ , Sue-Ann Mok ₁

Affiliation

tau 原纤维的积累与神经退行性疾病有关，统称为 tau 病。冷冻电镜研究表明，tau 蛋白的堆积原纤维核心在不同的 tau 蛋白病中采用不同的结构，例如阿尔茨海默病、皮质基底节变性和进行性核上性麻痹。一部分 tau 蛋白病与 tau 蛋白的错义突变有关，但尚不清楚这些突变是否影响 tau 纤维的结构。为了回答这个问题，我们开发了一个高通量蛋白质纯化平台，并使用全长 0N4R 剪接亚型纯化了一组 37 个 tau 变体。这些变体中的每一个都被用来在体外产生原纤维，并使用高通量蛋白酶敏感性平台研究它们的相关结构。我们发现，一部分与疾病相关的突变形成了类似于野生型 tau 蛋白的原纤维，而其他突变则截然不同。突变对 tau 结构的影响与突变位置或原纤维组装的相对动力学没有明显关联，这表明 tau 突变通过复杂的分子机制改变堆积的核心结构。总之，这些研究表明单点突变可以影响 tau 蛋白组装成原纤维，从而深入了解其与病理和疾病的关联。

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Disease-Associated Mutations in Tau Encode for Changes in Aggregate Structure Conformation

The accumulation of tau fibrils is associated with neurodegenerative diseases, which are collectively termed tauopathies. Cryo-EM studies have shown that the packed fibril core of tau adopts distinct structures in different tauopathies, such as Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy. A subset of tauopathies are linked to missense mutations in the tau protein, but it is not clear whether these mutations impact the structure of tau fibrils. To answer this question, we developed a high-throughput protein purification platform and purified a panel of 37 tau variants using the full-length 0N4R splice isoform. Each of these variants was used to create fibrils in vitro, and their relative structures were studied using a high-throughput protease sensitivity platform. We find that a subset of the disease-associated mutations form fibrils that resemble wild-type tau, while others are strikingly different. The impact of mutations on tau structure was not clearly associated with either the location of the mutation or the relative kinetics of fibril assembly, suggesting that tau mutations alter the packed core structures through a complex molecular mechanism. Together, these studies show that single-point mutations can impact the assembly of tau into fibrils, providing insight into its association with pathology and disease.

更新日期：2023-12-06

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