Transactive response DNA-binding protein 43 (TDP-43) regulates alternative splicing of tau exon 10: Implications for the pathogenesis of tauopathies
Transactive response DNA-binding protein 43 (TDP-43) regulates alternative splicing of tau exon 10: Implications for the pathogenesis of tauopathies
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交互反应 DNA 结合蛋白 43 (TDP-43) 调节 tau 外显子 10 的选择性剪接：对 tau 病发病机制的影响
DOI：
10.1074/jbc.m117.783498
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发表时间：
2017-06-23
影响因子：
4.8
通讯作者：
Liu, Fei
中科院分区：
文献类型：
--
作者：
Gu, Jianlan;Chen, Feng;Liu, Fei
神经元蛋白tau的过度磷酸化和聚集是导致被称为tau蛋白病的神经退行性疾病的原因。tau外显子10可变剪接的失调导致两种tau异构体（3R - tau和4R - tau）的比例改变，这在几种tau蛋白病中都有发现。43 kDa的反式作用DNA结合蛋白（TDP - 43）参与RNA加工的调控，包括剪接。在慢性创伤性脑病或阿尔茨海默病患者的大脑中观察到TDP - 43在细胞质中聚集，而在这些疾病中，过度磷酸化的tau神经原纤维缠结是其特征。在此，我们研究了TDP - 43在tau外显子10剪接中的作用。我们发现TDP - 43促进tau外显子10的包含，这增加了4R - tau异构体的产生。此外，TDP - 43能够与tau前体mRNA的内含子9结合。TDP - 43的N端或C端缺失促进其在细胞质中的聚集，并消除或减弱TDP - 43促进的tau外显子10包含。与肌萎缩侧索硬化或伴有泛素包涵体的额颞叶变性相关的几种TDP - 43突变比野生型TDP - 43更有效地促进tau外显子10包含，但在培养细胞中不影响TDP - 43的细胞质聚集。在表达人TDP - 43的转基因小鼠大脑中，3R - tau/4R - tau的比例降低，而在表达致病突变TDP - 43（M337V）的大脑中该比例升高，其中细胞质TDP - 43增加。这些发现表明，TDP - 43促进tau外显子10包含和4R - tau表达，并且TDP - 43的疾病相关变化（截断和突变）影响其在tau外显子10剪接中的功能，可能是由于TDP - 43错误定位到细胞质中。
Hyperphosphorylation and aggregation of the neuronal protein tau are responsible for neurodegenerative diseases called tauopathies. Dysregulation of the alternative splicing of tau exon 10 results in alterations of the ratio of two tau isoforms, 3R-tau and 4R-tau, which have been seen in several tauopathies. Transactive response DNA-binding protein of 43 kDa (TDP-43) is involved in the regulation of RNA processing, including splicing. Cytoplasmic aggregation of TDP-43 has been observed in the brains of individuals with chronic traumatic encephalopathy or Alzheimer's disease, diseases in which neurofibrillary tangles of hyperphosphorylated tau are hallmarks. Here, we investigated the role of TDP-43 in tau exon 10 splicing. We found that TDP-43 promoted tau exon 10 inclusion, which increased production of the 4R-tau isoform. Moreover, TDP-43 could bind to intron 9 of tau pre-mRNA. Deletion of the TDP-43 N or C terminus promoted its cytoplasmic aggregation and abolished or diminished TDP-43-promoted tau exon 10 inclusion. Several TDP-43 mutations associated with amyotrophic lateral sclerosis or frontotemporal lobar degeneration with ubiquitin inclusions promoted tau exon 10 inclusion more effectively than wild-type TDP-43 but did not affect TDP-43 cytoplasmic aggregation in cultured cells. The ratio of 3R-tau/4R-tau was decreased in transgenic mouse brains expressing human TDP-43 and increased in the brains expressing the disease-causing mutation TDP-43M337V, in which cytoplasmic TDP-43 was increased. These findings suggest that TDP-43 promotes tau exon 10 inclusion and 4R-tau expression and that disease-related changes of TDP-43, truncations and mutations, affect its function in tau exon 10 splicing, possibly because of TDP-43 mislocalization to the cytoplasm.