Abstract Details

Title Accelerated DNA Methylation Age of the TARDBP 3'UTR in the Motor Cortex is Associated with Age of Sporadic ALS Onset.

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P1 - Poster Session 1 (9:00 AM-5:00 PM)

Poster/Presentation
Number 373

Objective To determine the association between age of onset of sporadic amyotrophic lateral sclerosis (ALS) and DNA methylation of the TARDBP 3'UTR in the motor cortex.

Background Accelerated epigenetic age, derived from a genome-wide study, is associated with the age of onset of sporadic ALS. However, it remains unclear which ALS-related genes expression is associated with epigenetic aging. The main pathogenesis of sporadic ALS is the accumulation of TDP-43 in the cytoplasm. TDP-43 binds to its encoding TARDBP pre-mRNA, induces alternative splicing, and auto-regulates the expression. We found in our cell experiments that this auto-regulated splicing is affected by the DNA methylation of the TARDBP 3'UTR. Therefore, we hypothesized that the DNA methylation state during aging may be related to the age of sporadic ALS onset via increased TDP-43 expression.

Design/Methods We analyzed DNA methylation of TARDBP 3'UTR in the motor cortex of 10 patients with ALS and 11 controls without brain diseases. Moreover, we investigated the amount of TARDBP mRNA (8 ALS, 8 controls) and TDP-43 protein (5 ALS, 11 controls) from the same region. Finally, we evaluated the relationship between the age of ALS onset and DNA methylation of TARDBP 3'UTR.

Results In the motor cortex of the controls, six CpG sites in the TARDBP 3'UTR were demethylated with aging (r = 0.66), and TARDBP mRNA increased with demethylation (r = 0.80). In the analysis of 16 cases (5 ALS, 11 controls), insoluble TDP-43 increased with demethylation (r = 0.56). Accelerated age of DNA methylation in patients with ALS, calculated from the regression line between age and DNA methylation of the TARDBP 3'UTR in the control group, was inversely correlated with age of ALS onset (r = -0.84, p = 0.0025).

Conclusions Age of ALS onset is associated with an accelerated DNA methylation age of the TARDBP 3'UTR in the motor cortex.

Authors/Disclosures
Takuma Yamagishi, MD (Department of Neurology,Brain research institute, Niigata University) PRESENTER	Dr. Yamagishi has nothing to disclose.
	No disclosure on file
Akihiro Sugai, MD (Dept of Neurology, Clinical Neuroscience)	The institution of Dr. Sugai has received research support from Japan Society for the Promotion of Science. The institution of Dr. Sugai has received research support from SERIKA FUND. The institution of Dr. Sugai has received research support from Japan Agency for Medical Research and Development.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Tomohiko Ishihara	Tomohiko Ishihara has nothing to disclose.
	No disclosure on file
Mari Tada, MD, PhD (Niigata University, Brain Research Institute)	Dr. Tada has nothing to disclose.
Takeshi Ikeuchi, MD (Brain Research Institute, Niigata University)	Dr. Ikeuchi has nothing to disclose.
	No disclosure on file
Osamu Onodera, MD	Dr. Onodera has nothing to disclose.

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