人类运动皮层中 TDP-43 自身调节区的与年龄相关的去甲基化。

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

机构信息

Department of Neurology, Brain Research Institute, Niigata University, Niigata city, Japan.

Department of Molecular Neuroscience, Center for Bioresource-based Research, Brain Research Institute, Niigata University, Niigata city, Japan.

出版信息

Commun Biol. 2021 Sep 21;4(1):1107. doi: 10.1038/s42003-021-02621-0.

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.

在肌萎缩性侧索硬化症（ALS）中，TAR DNA 结合蛋白 43（TDP-43），由 TARDBP 编码，在运动皮层中形成聚集体。这种聚集的形成可能是由 TDP-43 水平随着年龄的增长而增加引发的。然而，TDP-43 的量通过 TARDBP 3'UTR 的选择性剪接进行自我调节，并且这种自我调节如何受到年龄的影响仍有待阐明。我们发现，TARDBP 3'UTR 中自我调节区域的 DNA 去甲基化减少了选择性剪接并增加了 TARDBP mRNA 的表达。此外，在人类运动皮层中，我们发现该区域随着年龄的增长而发生去甲基化，导致 TARDBP mRNA 的表达增加。运动皮层中 DNA 去甲基化的加速与 ALS 发病年龄有关。总之，运动皮层中与年龄相关的 DNA 去甲基化导致 TDP-43 自我调节的失调，可能解释了衰老和运动系统选择性在 ALS 中的作用。