PT  - JOURNAL ARTICLE
AU  - Yuka Koike
AU  - Akihiro Sugai
AU  - Norikazu Hara
AU  - Junko Ito
AU  - Akio Yokoseki
AU  - Tomohiko Ishihara
AU  - Takuma Yamagishi
AU  - Shintaro Tsuboguchi
AU  - Mari Tada
AU  - Takeshi Ikeuchi
AU  - Akiyoshi Kakita
AU  - Osamu Onodera
TI  - Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex
AID  - 10.1101/2021.01.13.426599
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.13.426599
4099  - http://biorxiv.org/content/early/2021/08/15/2021.01.13.426599.short
4100  - http://biorxiv.org/content/early/2021/08/15/2021.01.13.426599.full
AB  - In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43), which is encoded by TARDBP, forms aggregates in the motor cortex. This aggregate formation may be triggered by an increase in the TDP-43 level with aging. However, the amount of TDP-43 is autoregulated by alternative splicing of the TARDBP 3’UTR, and how this autoregulation is affected by aging remains to be elucidated. We found that DNA demethylation in the autoregulatory region in the TARDBP 3′UTR reduced alternative splicing and increased TARDBP mRNA expression. Furthermore, in the human motor cortex, we found that this region was demethylated with aging, resulting in increased expression of TARDBP mRNA. The acceleration of DNA demethylation in the motor cortex was associated with the age of ALS onset. In summary, the dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and motor system selectivity in ALS.Competing Interest StatementThe authors have declared no competing interest.