RNP2 of RNA recognition motif 1 plays a central role in the aberrant modification of TDP-43.
RNP2 of RNA recognition motif 1 plays a central role in the aberrant modification of TDP-43.
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DOI：
10.1371/journal.pone.0066966
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sobue G
中科院分区：
文献类型：
--
作者：
Takagi S;Iguchi Y;Katsuno M;Ishigaki S;Ikenaka K;Fujioka Y;Honda D;Niwa J;Tanaka F;Watanabe H;Adachi H;Sobue G
磷酸化和截短型TAR DNA结合蛋白-43(TDP-43)是肌萎缩侧索硬化症和额颞叶变性两种TDP-43蛋白病神经元和神经胶质细胞中泛素化胞浆包涵体的主要成分。因此，TDP-43的修饰被认为在TDP-43蛋白病的发病机制中起着重要作用。然而，这些异常修饰的最初原因以及导致其聚集的TDP-43区域仍然不确定。在这里，我们报告了TDP-43的32 kDa C-末端片段，它缺乏RNA结合基序1(RRM1)的RNP2基序，在培养细胞中形成聚集体，当RNP2基序在全长TDP-43中缺失或突变时，也获得了类似的表型。这些聚集体被泛素化、磷酸化和截断，并隔离了在TDP-43蛋白病患者神经元中看到的25 kDa C末端TDP-43片段。此外，与核糖核酸酶孵育降低了TDP-43在细胞裂解物中的溶解度。这些发现表明，RRM1的RNP2基序在TDP-43的病理修饰中起着重要作用，RNA结合的破坏可能是TDP-43聚集过程的基础。
Phosphorylated and truncated TAR DNA-binding protein-43 (TDP-43) is a major component of ubiquitinated cytoplasmic inclusions in neuronal and glial cells of two TDP-43 proteinopathies, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Modifications of TDP-43 are thus considered to play an important role in the pathogenesis of TDP-43 proteinopathies. However, both the initial cause of these abnormal modifications and the TDP-43 region responsible for its aggregation remain uncertain. Here we report that the 32 kDa C-terminal fragment of TDP-43, which lacks the RNP2 motif of RNA binding motif 1 (RRM1), formed aggregates in cultured cells, and that similar phenotypes were obtained when the RNP2 motif was either deleted from or mutated in full-length TDP-43. These aggregations were ubiquitinated, phosphorylated and truncated, and sequestered the 25 kDa C-terminal TDP-43 fragment seen in the neurons of TDP-43 proteinopathy patients. In addition, incubation with RNase decreased the solubility of TDP-43 in cell lysates. These findings suggest that the RNP2 motif of RRM1 plays a substantial role in pathological TDP-43 modifications and that it is possible that disruption of RNA binding may underlie the process of TDP-43 aggregation.
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影响因子：
3.7
作者：
Choi SI;Han KS;Kim CW;Ryu KS;Kim BH;Kim KH;Kim SI;Kang TH;Shin HC;Lim KH;Kim HK;Hyun JM;Seong BL
通讯作者：
Seong BL
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：
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：
2.9
作者：
Moisse, Katie;Volkening, Kathryn;Strong, Michael J.
通讯作者：
Strong, Michael J.
影响因子：
4.8
作者：
Fuentealba, Rodrigo A.;Udan, Maria;Baloh, Robert H.
通讯作者：
Baloh, Robert H.