XBP1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP-43 transgenic rats.
XBP1 depletion precedes ubiquitin aggregation and Golgi fragmentation in TDP-43 transgenic rats.
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DOI：
10.1111/jnc.12014
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发表时间：
2012-11
影响因子：
4.7
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Tong J;Huang C;Bi F;Wu Q;Huang B;Zhou H
蛋白包涵体是神经退行性疾病的一个显著特征，包括额颞叶变性（FTLD），其特征在于存在泛素化的TDP-43包涵体。蛋白质内含物的存在表明蛋白质降解机制的中断或错误折叠蛋白质的过载。为了应对错误折叠蛋白的增加，细胞通常启动一种称为未折叠蛋白反应（UPR）的机制，以减少内质网腔内的错误折叠蛋白。在这里，我们研究了突变TDP-43对转基因大鼠UPR的影响，这些转基因大鼠在前脑神经元中限制性表达突变人TDP-43。过度表达突变TDP-43在大鼠中引起突出的泛素聚集和显着的高尔基复合体的碎片神经元损失之前。虽然泛素聚集体和高尔基体片段积累，神经元表达突变TDP-43未能上调驻留在内质网中的伴侣蛋白，并未能启动UPR。在泛素聚集和高尔基体断裂之前，神经元耗尽了X-box结合蛋白1（XBP 1），这是UPR机制的关键参与者。虽然还需要确定TDP-43的突变如何导致UPR的失败，但我们的数据表明UPR的失败与TDP-43的发病机制有关。
Protein inclusion is a prominent feature of neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) that is characterized by the presence of ubiquitinated TDP-43 inclusion. Presence of protein inclusions indicates an interruption to protein degradation machinery or the overload of misfolded proteins. In response to the increase in misfolded proteins, cells usually initiate a mechanism called unfolded protein response (UPR) to reduce misfolded proteins in the lumen of endoplasmic reticules. Here we examined the effects of mutant TDP-43 on the UPR in transgenic rats that express mutant human TDP-43 restrictedly in the neurons of the forebrain. Overexpression of mutant TDP-43 in rats caused prominent aggregation of ubiquitin and remarkable fragmentation of Golgi complexes prior to neuronal loss. While ubiquitin aggregates and Golgi fragments were accumulating, neurons expressing mutant TDP-43 failed to upregulate chaperones residing in the endoplasmic reticules and failed to initiate the UPR. Prior to ubiquitin aggregation and Golgi fragmentation, neurons were depleted of X-box binding protein 1 (XBP1), a key player of UPR machinery. While it remains to determine how mutation of TDP-43 leads to the failure of the UPR, our data demonstrate that failure of the UPR is implicated in TDP-43 pathogenesis.
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影响因子：
3.5
作者：
Fujita, Eriko;Kouroku, Yoriko;Momoi, Takashi
通讯作者：
Momoi, Takashi
影响因子：
7.5
作者：
Lowe, Martin
通讯作者：
Lowe, Martin
影响因子：
4.5
作者：
Huang C;Zhou H;Tong J;Chen H;Liu YJ;Wang D;Wei X;Xia XG
通讯作者：
Xia XG
影响因子：
25
作者：
Tollervey, James R.;Curk, Tomaz;Rogelj, Boris;Briese, Michael;Cereda, Matteo;Kayikci, Melis;Koenig, Julian;Hortobagyi, Tibor;Nishimura, Agnes L.;Zupunski, Vera;Patani, Rickie;Chandran, Siddharthan;Rot, Gregor;Zupan, Blaz;Shaw, Christopher E.;Ule, Jernej
通讯作者：
Ule, Jernej
影响因子：
25
作者：
Polymenidou, Magdalini;Lagier-Tourenne, Clotilde;Hutt, Kasey R.;Huelga, Stephanie C.;Moran, Jacqueline;Liang, Tiffany Y.;Ling, Shuo-Chien;Sun, Eveline;Wancewicz, Edward;Mazur, Curt;Kordasiewicz, Holly;Sedaghat, Yalda;Donohue, John Paul;Shiue, Lily;Bennett, C. Frank;Yeo, Gene W.;Cleveland, Don W.
通讯作者：
Cleveland, Don W.