Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP.
Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP.
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内源性TDP-43而不是FUS，通过G3BP导致应力颗粒组件。
DOI：
10.1186/1750-1326-7-54
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发表时间：
2012-10-24
影响因子：
15.1
通讯作者：
Vande Velde C
中科院分区：
文献类型：
--
作者：
Aulas A;Stabile S;Vande Velde C
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是上下运动神经元选择性丧失，运动神经元这种细胞类型比其他细胞类型对外源性应激本质上更脆弱。长期以来，人们一直认为遗传易感性和环境毒素暴露之间的相互作用与ALS相关。克服应激的一种细胞机制是形成称为应激颗粒（SG）的小而致密的细胞质结构域，其中包含翻译停滞的mRNA。TDP - 43（由TARDBP编码）是一种导致ALS的基因，我们之前已表明它参与核心应激颗粒蛋白G3BP和TIA - 1的调控。在几乎所有应激条件下，TIA - 1和G3BP都定位于应激颗粒，并且被认为对应激颗粒的形成至关重要。在此，我们报道TDP - 43对于正常的应激颗粒动态是必需的，特别是以TIA - 1的二次聚集为标志的应激颗粒组装。我们还表明，应激颗粒组装（而非起始）需要G3BP。此外，G3BP可以挽救内源性TDP - 43缺失细胞中应激颗粒组装的缺陷。我们还证明，内源性TDP - 43和FUS在此细胞过程中没有重叠功能，因为在缺乏FUS的情况下应激颗粒的起始和组装正常发生。最后，我们观察到应激颗粒组装是神经元样细胞应对急性氧化应激存活的一个促成因素。这些数据提出了一种可能性，即核TDP - 43功能丧失导致正常应激颗粒动态的破坏可能导致ALS中的神经元脆弱性。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, a cell type that is intrinsically more vulnerable than other cell types to exogenous stress. The interplay between genetic susceptibility and environmental exposures to toxins has long been thought to be relevant to ALS. One cellular mechanism to overcome stress is the formation of small dense cytoplasmic domains called stress granules (SG) which contain translationally arrested mRNAs. TDP-43 (encoded by TARDBP) is an ALS-causative gene that we have previously implicated in the regulation of the core stress granule proteins G3BP and TIA-1. TIA-1 and G3BP localize to SG under nearly all stress conditions and are considered essential to SG formation. Here, we report that TDP-43 is required for proper SG dynamics, especially SG assembly as marked by the secondary aggregation of TIA-1. We also show that SG assembly, but not initiation, requires G3BP. Furthermore, G3BP can rescue defective SG assembly in cells depleted of endogenous TDP-43. We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation and assembly occur normally in the absence of FUS. Lastly, we observe that SG assembly is a contributing factor in the survival of neuronal-like cells responding to acute oxidative stress. These data raise the possibility that disruptions of normal stress granule dynamics by loss of nuclear TDP-43 function may contribute to neuronal vulnerability in ALS.
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影响因子：
4.2
作者：
Gal J;Zhang J;Kwinter DM;Zhai J;Jia H;Jia J;Zhu H
通讯作者：
Zhu H
影响因子：
3.7
作者：
Liu-Yesucevitz L;Bilgutay A;Zhang YJ;Vanderweyde T;Citro A;Mehta T;Zaarur N;McKee A;Bowser R;Sherman M;Petrucelli L;Wolozin B
通讯作者：
Wolozin B
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
10.5
作者：
Damgaard, Christian Kroun;Lykke-Andersen, Jens
通讯作者：
Lykke-Andersen, Jens
影响因子：
3.3
作者：
Didiot, Marie-Cecile;Subramanian, Murugan;Moine, Herve
通讯作者：
Moine, Herve