TDP-43
TARDBP encodes TDP-43, a protein that is central to the biology of most ALS cases and a large proportion of FTD. Even in patients without TARDBP mutations, TDP-43 pathology is present, making it one of the most important proteins in neurodegeneration.
Normal function
TDP-43 is a nuclear RNA-binding protein that regulates RNA splicing, stability, transport, and translation. It is essential for maintaining proper gene expression and is particularly important in neurons, where precise RNA regulation is required for synaptic function and cellular maintenance.
Mutation and effect
Under disease conditions, TDP-43 is mislocalized from the nucleus to the cytoplasm, where it forms insoluble aggregates. This results in both loss of nuclear function and toxic gain of function in the cytoplasm. When TDP-43 isn’t in the nucleus, RNA can be spliced differently to include things that are normally removed in a process called cryptic exon inclusion. The result of this is that proteins that are important for neurons to function properly, like UNC13A and STMN2, have lower levels and are less functional. But the RNA misprocessing is widespread, affecting hundreds of gene transcripts.
Implications for treatment
Although TARDBP mutations make up a minority of familial ALS cases, TDP-43 pathology is found in the majority of ALS cases and roughly half of FTD cases, making it a unifying feature across diseases. It is considered a central driver of pathology rather than a secondary byproduct.
Targeting TDP-43 is challenging because it is essential for normal cell function. Therapeutic approaches must balance restoring normal localization and preventing aggregation without disrupting its critical RNA-regulatory roles.
Research focus
One major focus is understanding what causes TDP-43 to leave the nucleus, accumulate in the cytoplasm, and form aggregates. This includes studying stress granules, impaired protein clearance, nuclear transport defects, phosphorylation, cleavage, and other post-translational modifications.
A second major focus is identifying the most important downstream effects of TDP-43 loss of function. TDP-43 regulates many RNA targets, but not all are equally relevant to disease. Genes such as STMN2 and UNC13A have become especially important because their misprocessing may directly affect axon maintenance and synaptic function. Therapeutically, researchers are exploring ways to restore nuclear TDP-43 function, prevent aggregation, correct specific splicing defects, and develop biomarkers that can detect TDP-43 pathology in living patients.
Sources
- Neumann, M., Sampathu, D. M., Kwong, L. K., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
- Kabashi, E., Valdmanis, P. N., Dion, P., et al. (2008). TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.
- Ma, X. R., Prudencio, M., Koike, Y., et al. (2022). TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.
- Balendra, R., et al. (2025). Amyotrophic lateral sclerosis caused by TARDBP mutations.