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

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. In order to assess the effects of aging on the autoregulation of TAR DNA-binding protein 43 (TDP-43) and the potential effects of this on the role of TDP-43 in Amyotrophic Lateral Sclerosis (ALS), Koike et al examined post-mortem motor cortex tissue from ALS patients. They found that DNA demethylation in the autoregulatory region of the TARDBP 3′UTR, which encodes TDP-43, increased with age and was associated with the onset age of ALS and thus could be indicative of a role for dysregulation of TDP-43 autoregulation in ALS pathology.