ArticleJournal of cell science2020
TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2.
Article in Journal of cell science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 22 citations in OpenAlex.
- Tankyrases and Their Binding Proteins: Origins of Their Roles in Diverse Cellular Pathways.Cells · 2026Review
- Aberrant NSUN1 activity connects mLife science alliance · 2026Article
- Synaptopathy in the TDP-43ΔNLS Mouse Model of Sporadic Amyotrophic Lateral Sclerosis.The European journal of neuroscience · 2025Article
- Regulation of Biomolecular Condensates by Poly(ADP-ribose).Chemical reviews · 2023Review
- Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology.Scientific reports · 2022Article
- Poly(ADP-ribose) drives condensation of FUS via a transient interaction.Molecular cell · 2022Article
- Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence.Human molecular genetics · 2021Article
- Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities.Journal of experimental & clinical cancer research : CR · 2021Review
- Genome-Wide Meta-Analysis Identifies Two Novel Risk Loci for Epilepsy.Frontiers in neuroscience · 2021Article
- Altered Phase Separation and Cellular Impact inFrontiers in cellular neuroscience · 2021Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
In >95% of cases of amyotrophic lateral sclerosis (ALS) and ∼45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes tankyrase 1 and tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. Thus, Tnks-1/2 activity modulates TDP-43 and is a potential therapeutic target in diseases associated with TDP-43, such as ALS and FTD.This article has an associated First Person interview with the first author of the paper.
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Registered trials
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