USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells
USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells
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DOI：
10.1038/s41598-019-47033-7
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发表时间：
2019-07-22
影响因子：
4.6
通讯作者：
Fujii, Masahiro
中科院分区：
文献类型：
--
作者：
Piatnitskaia, Svetlana;Takahashi, Masahiko;Fujii, Masahiro
脑损伤的神经元中的Tau聚集体是包括阿尔茨海默病（AD）在内的Tau病的标志性病理学。最近的研究表明，RNA结合蛋白TIA 1通过诱导含有Tau的应激颗粒（SG）的形成来启动Tau聚集。SGs是应激诱导的细胞质蛋白聚集体，含有许多RNA结合蛋白，其被认为是多种神经退行性疾病中多种致病蛋白聚集体的起始位点。在这项研究中，我们发现泛素特异性蛋白酶10（USP 10）是Tau/TIA 1/USP 10阳性SG形成的关键因素。在HT 22神经元细胞中，蛋白酶体抑制或TIA 1过表达诱导TIA 1/Tau阳性SG的形成，并且通过USP 10的消耗严重减弱该形成。此外，在没有应激刺激的情况下，HT 22细胞中USP 10的过表达以不依赖于去遍在蛋白酶的方式诱导TIA 1/Tau/USP 10阳性SG。在AD脑病变中，USP 10与神经元细胞体中的Tau聚集体共定位。目前的研究结果表明，USP 10通过SG形成在AD中的致病性Tau聚集的起始中起关键作用。
Tau aggregates in neurons of brain lesions is a hallmark pathology of tauopathies, including Alzheimer's disease (AD). Recent studies suggest that the RNA-binding protein TIA1 initiates Tau aggregation by inducing the formation of stress granules (SGs) containing Tau. SGs are stress-inducible cytoplasmic protein aggregates containing many RNA-binding proteins that has been implicated as an initial site of multiple pathogenic protein aggregates in several neurodegenerative diseases. In this study, we found that ubiquitin-specific protease 10 (USP10) is a critical factor for the formation of Tau/TIA1/USP10-positive SGs. Proteasome inhibition or TIA1-overexpression in HT22 neuronal cells induced the formation of TIA1/Tau-positive SGs, and the formations were severely attenuated by depletion of USP10. In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner. In AD brain lesions, USP10 was colocalized with Tau aggregates in the cell body of neurons. The present findings suggest that USP10 plays a key role in the initiation of pathogenic Tau aggregation in AD through SG formation.