2016.06.08
Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43
（Nucleic Acids Res. 2016 Jul 8;44(12):5820-36. doi: 10.1093/nar/gkw499.）
Akihide Koyama1,2,†, Akihiro Sugai1,†, Taisuke Kato3,†, Tomohiko Ishihara3, Atsushi Shiga1,2, Yasuko Toyoshima4, Misaki Koyama1, Takuya Konno1, Sachiko Hirokawa3, Akio Yokoseki3, Masatoyo Nishizawa1, Akiyoshi Kakita5, Hitoshi Takahashi4 and Osamu Onodera1
†These authors contributed equally to the paper as first authors.
1Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University
2Center for Transdisciplinary Research, Niigata University
3Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, Niigata University
4Department of Pathology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University
5Department of Pathology, Center for Bioresource-based Research, Brain Research Institute, Niigata University
Abstract
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.
