Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.
Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.
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DOI：
10.1093/nar/gkw499
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发表时间：
2016-07-08
影响因子：
14.9
通讯作者：
Onodera O
中科院分区：
文献类型：
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作者：
Koyama A;Sugai A;Kato T;Ishihara T;Shiga A;Toyoshima Y;Koyama M;Konno T;Hirokawa S;Yokoseki A;Nishizawa M;Kakita A;Takahashi H;Onodera O
肌萎缩侧索硬化症（ALS）是一种致命的运动神经元疾病。在ALS的运动神经元中，TAR DNA结合蛋白-43（TDP-43），一种由TARDBP编码的核蛋白，从核中缺失并形成胞质内含物。TDP-43通过调节TARDBP mRNA来自动调节量，TARDBP mRNA在最后一个外显子内具有三个多聚腺苷酸化信号（PAS）和三个额外的替代内含子。然而，目前还不清楚自动调节机制如何工作，以及没有TDP-43核的ALS运动神经元的自动调节状态如何。在这里，我们表明，TDP-43抑制最接近的PAS的选择，并诱导剪接的多个选择性内含子在TARDBP mRNA的无义介导的mRNA衰减，以减少细胞质TARDBP mRNA的量。当TDP-43耗尽时，TARDBP mRNA使用最近端PAS并在细胞质中增加。最后，我们已经证明，在ALS运动神经元，特别是与错误定位TDP-43的神经元，TARDBP mRNA的量在细胞质中增加。我们的观察表明，核TDP-43有助于自动调节，并表明核TDP-43的缺乏诱导异常的自动调节，并增加TARDBP mRNA的量。恶性循环可能加速ALS的疾病进展。
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons—especially neurons with mislocalized TDP-43—the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.