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.

中文翻译：

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人类运动皮层中 TDP-43 自动调节区域的年龄相关去甲基化

在肌萎缩侧索硬化 (ALS) 中，由TARDBP编码的 TAR DNA 结合蛋白 43 (TDP-43)在运动皮层中形成聚集体。这种聚集体的形成可能是由随着衰老而增加的 TDP-43 水平引发的。然而，TDP-43 的量是通过TARDBP 3'UTR的选择性剪接自动调节的，而这种自动调节如何受衰老影响仍有待阐明。我们发现 TARDBP 3'UTR 中自动调节区域的 DNA 去甲基化减少了选择性剪接并增加了TARDBP mRNA 表达。此外，在人类运动皮层中，我们发现该区域随着衰老而去甲基化，导致TARDBP 的表达增加mRNA。运动皮层 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 去甲基化对 TDP-43 自动调节的失调可以解释衰老和运动系统选择性在 ALS 中的作用。