Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
21 09 2021
21 09 2021
Historique:
received:
21
01
2021
accepted:
01
09
2021
entrez:
22
9
2021
pubmed:
23
9
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34548609
doi: 10.1038/s42003-021-02621-0
pii: 10.1038/s42003-021-02621-0
pmc: PMC8455575
doi:
Substances chimiques
DNA-Binding Proteins
0
TARDBP protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1107Informations de copyright
© 2021. The Author(s).
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