Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex
Open Access
- 21 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Communications Biology
- Vol. 4 (1), 1-11
- https://doi.org/10.1038/s42003-021-02621-0
Abstract
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.This publication has 61 references indexed in Scilit:
- Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognitionCell Research, 2013
- Divergent Whole-Genome Methylation Maps of Human and Chimpanzee Brains Reveal Epigenetic Basis of Human Regulatory EvolutionAmerican Journal of Human Genetics, 2012
- Distinct DNA methylomes of newborns and centenariansProceedings of the National Academy of Sciences of the United States of America, 2012
- Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applicationsBioinformatics, 2011
- Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43Nature Neuroscience, 2011
- Distinct DNA methylation changes highly correlated with chronological age in the human brainHuman Molecular Genetics, 2011
- TDP-43 regulates its mRNA levels through a negative feedback loopThe EMBO Journal, 2010
- Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-UThe Journal of Experimental Medicine, 2010
- TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathyActa Neuropathologica, 2009
- Protein aggregation and neurodegenerative diseaseNature Medicine, 2004