論文

2021年1月14日

Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex

  • Yuka Koike
  • ,
  • Akihiro Sugai
  • ,
  • Norikazu Hara
  • ,
  • Junko Ito
  • ,
  • Akio Yokoseki
  • ,
  • Tomohiko Ishihara
  • ,
  • Takuma Yamagishi
  • ,
  • Shintaro Tsuboguchi
  • ,
  • Mari Tada
  • ,
  • Takeshi Ikeuchi
  • ,
  • Akiyoshi Kakita
  • ,
  • Osamu Onodera

DOI
10.1101/2021.01.13.426599
出版者・発行元
Cold Spring Harbor Laboratory

<title>Abstract</title>In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43) forms aggregates in the motor cortex of the aging brain. This aggregate formation may be triggered by the increase in TDP-43 levels with aging. However, the amount of TDP-43 is autoregulated by the alternative splicing of the <italic>TARDBP</italic> 3’UTR, and its relationship with aging remains unresolved. Since DNA methylation is altered during aging, we hypothesized that 3’UTR methylation is also altered in the aging motor cortex, disrupting this autoregulatory system and increasing TDP-43 levels. We found that DNA demethylation in the autoregulatory region of TDP-43 reduced alternative splicing and increased TDP-43 expression. Furthermore, in the human motor cortex, we found that this region was demethylated with age and that the expression of TDP-43 increased. The dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and system selectivity in ALS.

リンク情報
DOI
https://doi.org/10.1101/2021.01.13.426599
URL
https://syndication.highwire.org/content/doi/10.1101/2021.01.13.426599
ID情報
  • DOI : 10.1101/2021.01.13.426599

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