Neuroscience researchMay 9, 2024

Molecular links between loss of TDP-43 function and genes related to ALS and frontotemporal dementia

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 25, 2026

Abstract

TDP-43 function is linked to ALS/FTD, with a focus on its role in splicing UNC13A and the effects of aging on TARDBP regulation.

Single nucleotide polymorphisms in UNC13A are the most common risk factors for ALS/FTD.
TDP-43 represses the inclusion of a 'cryptic exon' during the splicing of UNC13A RNA.
A risk-associated SNP in UNC13A leads to increased RNA levels by retaining the cryptic exon.
Aging may disrupt TDP-43 autoregulation through age-related DNA demethylation.
Altered TARDBP methylation due to aging reduces splicing efficiency and increases TARDBP mRNA levels.
Demethylation in the human motor cortex with aging is associated with the early onset of ALS.

Simplified

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion and cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43). TDP-43 plays a key role in regulating the splicing of numerous genes, including TARDBP. This review aims to delineate two aspects of ALS/FTD pathogenesis associated with TDP-43 function. First, we described novel mechanistic insights into the splicing of UNC13A, a TDP-43 target gene. Single nucleotide polymorphisms (SNPs) in UNC13A are the most common risk factors for ALS/FTD. We found that TDP-43 represses "cryptic exon" inclusion during UNC13A RNA splicing. A risk-associated SNP in this exon results in increased RNA levels of UNC13A retaining the cryptic exon. Second, we described the perturbation of the TDP-43 autoregulatory mechanism caused by age-related DNA demethylation. Aging is a major risk factor for sporadic ALS/FTD. Typically, TDP-43 levels are regulated via alternative splicing of TARDBP mRNA. This review focused on that TARDBP methylation is altered by aging, thereby disrupting TDP-43 autoregulation. It was found that demethylation reduces the efficiency of alternative splicing and increases TARDBP mRNA levels. Moreover, we demonstrated that, with aging, this region is demethylated in the human motor cortex and is associated with the early onset of ALS.

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Declaration of Competing Interest The authors declare no competing interests.

PubMed

Molecular links between loss of TDP-43 function and genes related to ALS and frontotemporal dementia

Abstract

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