||Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.
Koyama, Akihide小山, 哲秀
学位の種類: 博士（医学）. 報告番号: 乙第2205号. 学位記番号: 新大院博（医）乙第1784号. 学位授与年月日: 平成29年3月23日
Nucleic Acids Research 2016, 44(12) 5820-36
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 threeadditional 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 bservations 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.