Asparagine residue 368 is involved in Alzheimer's disease tau strain–specific aggregation
Asparagine residue 368 is involved in Alzheimer's disease tau strain–specific aggregation
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DOI：
10.1002/alz.047498
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发表时间：
2020-08
期刊：
影响因子：
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通讯作者：
S. Shimonaka;S. Matsumoto;Montasir Elahi;K. Ishiguro;M. Hasegawa;N. Hattori;Y. Motoi
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文献类型：
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作者：
S. Shimonaka;S. Matsumoto;Montasir Elahi;K. Ishiguro;M. Hasegawa;N. Hattori;Y. Motoi
在tau蛋白病中，tau形成具有不同构象的致病原纤维（称为“tau株”），并充当聚集“种子”模板，将正常tau转化为同构原纤维。先前的研究表明，tau纤维的聚集核心覆盖C-末端区域（243-406个氨基酸（aa）），并且在疾病之间存在差异。然而，不同的纤维状结构通过模板聚集形成和遗传的机制仍然未知。在这里，我们试图确定种子依赖性聚集的关键序列。为了鉴定缺失减少tau聚集的序列，将表达一系列10个部分缺失的SH-SY 5 Y细胞转染至细胞。（Del 1-10，覆盖244-400 aa）tau-CTF 24的突变体（243-441 aa）用从不同tau蛋白病患者的脑制备的tau种子处理（阿尔茨海默病、进行性核上性麻痹和皮质基底节变性）或重组tau蛋白，然后用生物化学方法评估种子依赖性tau蛋白聚集。我们发现缺失353-368 aa的Del 8突变体在细胞和体外模型中均显示出显著降低的聚集。此外，为了鉴定负责tau聚集的最小序列，我们系统地重复了细胞tau聚集测定以描绘较短的缺失位点，并揭示Asn-368突变抑制由AD tau种子触发的tau聚集，但不使用其他tau蛋白病种子。我们的研究表明，353-368 aa是一个新的聚集负责序列以外的PHF 6和PHF 6 *，在这个序列中，Asn-368残基在不同的tau蛋白病的菌株特异性tau蛋白聚集中发挥作用。
In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed “tau strains”) and acts as an aggregation “seed” templating the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the C-terminal region (243–406 amino acids (aa)) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited via templated aggregation are still unknown. Here, we sought to identify the key sequences of seed-dependent aggregation. To identify sequences for which deletion reduces tau aggregation, SH-SY5Y cells expressing a series of 10 partial deletion (Del 1–10, covering 244–400 aa) mutants of tau-CTF24 (243–441 aa) were treated with tau seeds prepared from a different tauopathy patient's brain (Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration) or recombinant tau, and then seed-dependent tau aggregation was assessed biochemically. We found that the Del 8 mutant lacking 353–368 aa showed significantly decreased aggregation in both cellular and in vitro models. Furthermore, to identify the minimum sequence responsible for tau aggregation, we systematically repeated cellular tau aggregation assays for the delineation of shorter deletion sites and revealed that Asn-368 mutation suppressed tau aggregation triggered by an AD tau seed, but not using other tauopathy seeds. Our study suggested that 353–368 aa is a novel aggregation-responsible sequence other than PHF6 and PHF6*, and within this sequence, the Asn-368 residue plays a role in strain-specific tau aggregation in different tauopathies.