The extreme N-terminus of TDP-43 mediates the cytoplasmic aggregation of TDP-43 and associated toxicity in vivo.
The extreme N-terminus of TDP-43 mediates the cytoplasmic aggregation of TDP-43 and associated toxicity in vivo.
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DOI：
10.1016/j.brainres.2016.04.069
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发表时间：
2016-09-15
期刊：
影响因子：
2.9
通讯作者：
Zhang, Yong-Jie
中科院分区：
文献类型：
--
作者：
Sasaguri, Hiroki;Chew, Jeannie;Xu, Ya-Fei;Gendron, Tania F.;Garrett, Aliesha;Lee, Chris W.;Jansen-West, Karen;Bauer, Peter O.;Perkerson, Emilie A.;Tong, Jimei;Stetler, Caroline;Zhang, Yong-Jie
Tar DNA结合蛋白43（TDP-43）的包涵体是肌萎缩侧索硬化（ALS）和具有TDP-43阳性包涵体的额颞叶变性（FTLD-TDP）的病理学标志。病理性TDP-43表现出疾病特异性的生化特征，包括其泛素化、磷酸化和截短。最近，我们证明了TDP-43的极端N-末端调节培养细胞和原代神经元中异常胞质TDP-43聚集的形成。然而，尚不清楚该N-末端结构域是否介导TDP-43聚集和相关的体内毒性。为了研究这一点，我们通过腺相关病毒（AAV）载体在小鼠原代皮层神经元和小鼠中枢神经系统中表达了具有核定位信号突变（GFP-TDP-43 NLSm）和没有末端N末端的截短形式（GFP-TDP-4310-414-NLSm）的GFP标记的TDP-43。与仅含GFP的神经元相比，GFP-TDP-43 NLSm的表达导致形成泛素阳性的细胞质内含物和caspase-3的活化，caspase-3是细胞死亡的指示物。此外，表达GFP-TDP-43 NLSm蛋白的小鼠表现出反应性神经胶质增生并出现神经异常。然而，通过缺失TDP-43的极端N-末端，这些病理学改变可以被消除。总之，我们的研究提供了进一步的证据，证实了TDP-43的极端N-末端在调节蛋白质结构以及介导与其聚集相关的毒性方面的关键作用。
Inclusions of Tar DNA- binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP). Pathological TDP-43 exhibits the disease-specific biochemical signatures, which include its ubiquitination, phosphorylation and truncation. Recently, we demonstrated that the extreme N-terminus of TDP-43 regulates formation of abnormal cytoplasmic TDP-43 aggregation in cultured cells and primary neurons. However, it remained unclear whether this N-terminal domain mediates TDP-43 aggregation and the associated toxicity in vivo. To investigate this, we expressed a GFP-tagged TDP-43 with a nuclear localization signal mutation (GFP-TDP-43NLSm) and a truncated form without the extreme N-terminus (GFP-TDP-4310-414-NLSm) by adeno-associated viral (AAV) vectors in mouse primary cortical neurons and murine central nervous system. Compared to neurons containing GFP alone, expression of GFP-TDP-43NLSm resulted in the formation of ubiquitin-positive cytoplasmic inclusions and activation of caspase-3, an indicator of cell death. Moreover, mice expressing GFP-TDP-43NLSm proteins show reactive gliosis and develop neurological abnormalities. However, by deletion of TDP-43’s extreme N-terminus, these pathological alterations can be abrogated. Together, our study provides further evidence confirming the critical role of the extreme N-terminus of TDP-43 in regulating protein structure as well as mediating toxicity associated with its aggregation.
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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：
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作者：
Buratti, Emanuele;De Conti, Laura;Baralle, Francisco
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Baralle, Francisco
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34.7
作者：
Lee, Edward B.;Lee, Virginia M-Y;Trojanowski, John Q.
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Trojanowski, John Q.
影响因子：
3.5
作者：
Janssens J;Van Broeckhoven C
通讯作者：
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影响因子：
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作者：
Kuo PH;Doudeva LG;Wang YT;Shen CK;Yuan HS
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Yuan HS