Increased cytoplasmicTARDBPmRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43
| Autor: | Sachiko Hirokawa, Yasuko Toyoshima, Hitoshi Takahashi, Akihide Koyama, Masatoyo Nishizawa, Osamu Onodera, Akio Yokoseki, Atsushi Shiga, Akiyoshi Kakita, Tomohiko Ishihara, Misaki Koyama, Takuya Konno, Taisuke Kato, Akihiro Sugai |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cytoplasm RNA Stability Biology TARDBP 03 medical and health sciences Exon mental disorders Genetics medicine Humans Autoregulation RNA Messenger Amyotrophic lateral sclerosis Nuclear protein Molecular Biology Cell Nucleus Feedback Physiological Motor Neurons Amyotrophic Lateral Sclerosis nutritional and metabolic diseases Exons Motor neuron medicine.disease Molecular biology Introns nervous system diseases DNA-Binding Proteins Cell nucleus HEK293 Cells 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Spinal Cord RNA splicing Signal Transduction |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkw499 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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