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Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.
http://hdl.handle.net/10191/47632
http://hdl.handle.net/10191/47632e8a4c28a-13a7-4487-aa99-a5c2407016f7
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要旨 (183.0 kB)
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Item type | 学位論文 / Thesis or Dissertation(1) | |||||
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公開日 | 2018-09-11 | |||||
タイトル | ||||||
タイトル | Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源 | http://purl.org/coar/resource_type/c_46ec | |||||
タイプ | thesis | |||||
その他のタイトル | ||||||
その他のタイトル | ALSではTDP-43量調節機構の破綻により,運動神経細胞のTARDBP mRNAが細胞質で増加する | |||||
著者 |
Koyama, Akihide
× Koyama, Akihide |
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著者別名 | ||||||
識別子 | 51110 | |||||
識別子Scheme | WEKO | |||||
姓名 | 小山, 哲秀 | |||||
抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | 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\nadditional 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. | |||||
内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 学位の種類: 博士(医学). 報告番号: 乙第2205号. 学位記番号: 新大博(医)乙第1784号. 学位授与年月日: 平成29年3月23日 | |||||
内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Nucleic Acids Research 2016, 44(12) 5820-36 | |||||
書誌情報 | 発行日 2017-03-23 | |||||
出版者 | ||||||
出版者 | 新潟大学 | |||||
DOI | ||||||
識別子タイプ | DOI | |||||
関連識別子 | info:doi/10.1093/nar/gkw499 | |||||
著者版フラグ | ||||||
値 | ETD | |||||
学位名 | ||||||
学位名 | 博士(医学) | |||||
学位授与機関 | ||||||
学位授与機関名 | 新潟大学 | |||||
学位授与年月日 | ||||||
学位授与年月日 | 2017-03-23 | |||||
学位授与番号 | ||||||
学位授与番号 | 13101乙第2205号 | |||||
学位記番号 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 新大博(医)乙第1784号 |