RT Journal Article
SR Electronic
T1 Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.13.426599
DO 10.1101/2021.01.13.426599
A1 Yuka Koike
A1 Akihiro Sugai
A1 Norikazu Hara
A1 Junko Ito
A1 Akio Yokoseki
A1 Tomohiko Ishihara
A1 Takuma Yamagishi
A1 Shintaro Tsuboguchi
A1 Mari Tada
A1 Takeshi Ikeuchi
A1 Akiyoshi Kakita
A1 Osamu Onodera
YR 2021
UL http://biorxiv.org/content/early/2021/08/15/2021.01.13.426599.abstract
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.