C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress.
C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress.
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DOI：
10.1186/1750-1326-6-57
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发表时间：
2011-08-08
影响因子：
15.1
通讯作者：
White AR
中科院分区：
文献类型：
--
作者：
Meyerowitz J;Parker SJ;Vella LJ;Ng DCh;Price KA;Liddell JR;Caragounis A;Li QX;Masters CL;Nonaka T;Hasegawa M;Bogoyevitch MA;Kanninen KM;Crouch PJ;White AR
TDP-43蛋白质病的特征是细胞核TDP-43表达丧失以及C末端TDP-43片段化和细胞质中积累的形成。最近的研究表明，TDP-43可以在响应细胞应激的RNA应激颗粒（SG）中积累，这可能与随后TDP-43泛素化蛋白聚集体的形成有关。然而，控制内源性TDP-43在慢性疾病期间在SG中积累的初始机制尚不清楚。在这项研究中，我们研究了TDP-43的加工和积累在SG中的SH-SY 5 Y神经元样细胞暴露于慢性氧化应激的机制。用线粒体抑制剂百草枯处理细胞培养物过夜，并检查TDP-43和SG处理。我们发现百草枯诱导的轻度胁迫导致TDP-43和HuR阳性SG的形成，其中一部分是泛素化的。TDP-43与SGs的共定位可以通过抑制c-Jun N-末端激酶（JNK）来完全阻止。JNK抑制不能阻止HuR阳性SG的形成，也不能阻止TDP-43在胞质溶胶中的扩散积累。相反，ERK或p38抑制阻止TDP-43和HuR阳性SG的形成。JNK抑制还抑制了用亚砷酸钠急性处理的细胞中的TDP-43 SG定位，并减少了用C-末端TDP-43 162-414和219-414构建体转染的培养物中每个细胞的聚集体数量。我们的研究首次证明了激酶控制TDP-43在SG中蓄积的关键作用，并可能对FTD和ALS治疗的开发具有重要意义，靶向TDP-43聚集的细胞信号通路控制。
TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 expression and formation of C-terminal TDP-43 fragmentation and accumulation in the cytoplasm. Recent studies have shown that TDP-43 can accumulate in RNA stress granules (SGs) in response to cell stresses and this could be associated with subsequent formation of TDP-43 ubiquinated protein aggregates. However, the initial mechanisms controlling endogenous TDP-43 accumulation in SGs during chronic disease are not understood. In this study we investigated the mechanism of TDP-43 processing and accumulation in SGs in SH-SY5Y neuronal-like cells exposed to chronic oxidative stress. Cell cultures were treated overnight with the mitochondrial inhibitor paraquat and examined for TDP-43 and SG processing. We found that mild stress induced by paraquat led to formation of TDP-43 and HuR-positive SGs, a proportion of which were ubiquitinated. The co-localization of TDP-43 with SGs could be fully prevented by inhibition of c-Jun N-terminal kinase (JNK). JNK inhibition did not prevent formation of HuR-positive SGs and did not prevent diffuse TDP-43 accumulation in the cytosol. In contrast, ERK or p38 inhibition prevented formation of both TDP-43 and HuR-positive SGs. JNK inhibition also inhibited TDP-43 SG localization in cells acutely treated with sodium arsenite and reduced the number of aggregates per cell in cultures transfected with C-terminal TDP-43 162-414 and 219-414 constructs. Our studies are the first to demonstrate a critical role for kinase control of TDP-43 accumulation in SGs and may have important implications for development of treatments for FTD and ALS, targeting cell signal pathway control of TDP-43 aggregation.
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DOI：
10.1097/nen.0b013e3181db8100
发表时间：
2010-05
影响因子：
3.2
作者：
Choi WS;Abel G;Klintworth H;Flavell RA;Xia Z
通讯作者：
Xia Z
影响因子：
38.1
作者：
Chen-Plotkin, Alice S.;Lee, Virginia M. -Y.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
4.4
作者：
Chang, Jing-Wen;Koike, Toru;Iwashima, Makio
通讯作者：
Iwashima, Makio
DOI：
10.1016/j.bbapap.2009.11.002
发表时间：
2010-03-01
影响因子：
3.2
作者：
Bogoyevitch, Marie A.;Ngoei, Kevin R. W.;Ng, Dominic C. H.
通讯作者：
Ng, Dominic C. H.
影响因子：
2.1
作者：
Ferrari R;Kapogiannis D;Huey ED;Momeni P
通讯作者：
Momeni P