論文

査読有り 国際誌
2019年10月

Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation.

Neurobiology of disease
  • Akihiro Sugai
  • ,
  • Taisuke Kato
  • ,
  • Akihide Koyama
  • ,
  • Yuka Koike
  • ,
  • Takuya Konno
  • ,
  • Tomohiko Ishihara
  • ,
  • Osamu Onodera

130
開始ページ
104534
終了ページ
104534
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.nbd.2019.104534

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.

リンク情報
DOI
https://doi.org/10.1016/j.nbd.2019.104534
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31310801

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