ArticleMolecular neurodegeneration2020
Impaired NHEJ repair in amyotrophic lateral sclerosis is associated with TDP-43 mutations.
Article in Molecular neurodegeneration, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 2 of them syntheses that pooled it.
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Who cites it
65 citing papers in PubMed, 2 syntheses or guidelines pooled it, 115 citations in OpenAlex.
- TDP-43 related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review and narrative synthesis.Frontiers in molecular neuroscience · 2026Pooled it
- C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.Frontiers in molecular neuroscience · 2025Pooled it
- Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43Antioxidants (Basel, Switzerland) · 2026Article
- Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems.Cell death & disease · 2026Article
- Calretinin and Parvalbumin Trapping of TDP43 and XRCC1 Instructs Neocortical Interneuron Death in Neonatal Hypoxic-Ischemic Encephalopathy.Biomolecules · 2026Article
- Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.Frontiers in pharmacology · 2026Review
- The Ku80-p53-SIRT1 axis in DNA damage response contributes to sporadic and familial ALS and FTD.Nature communications · 2025Article
- LINE-1 retrotransposition in a mouse TDP-43 model of neurodegeneration marks motor cortex neurons for cell-intrinsic and cell non-autonomous programmed cell death.PLoS genetics · 2025Article
- PIAS1/PIAS4-Mediated SUMOylation of TDP-43 Is Induced by Oxidative Stress.bioRxiv : the preprint server for biology · 2025Article
- Review
- Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.Pharmacological reviews · 2025Review
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- Targets and Gene Therapy of ALS (Part 1).International journal of molecular sciences · 2025Review
- Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.bioRxiv : the preprint server for biology · 2025Article
- Utilization of natural products in diverse pathogeneses of diseases associated with single or double DNA strand damage repair.Chinese medicine · 2025Review
- Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.Acta neuropathologica communications · 2025Article
- Review
- DNA Damage and Chromatin Rearrangement Work Together to Promote Neurodegeneration.Molecular neurobiology · 2025Review
- Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.Acta neuropathologica communications · 2024Review
- Proteins Associated with Neurodegenerative Diseases: Link to DNA Repair.Biomedicines · 2024Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPathological forms of TAR DNA-binding protein 43 (TDP-43) are present in motor neurons of almost all amyotrophic lateral sclerosis (ALS) patients, and mutations in TDP-43 are also present in ALS. Loss and gain of TDP-43 functions are implicated in pathogenesis, but the mechanisms are unclear. While the RNA functions of TDP-43 have been widely investigated, its DNA binding roles remain unclear. However, recent studies have implicated a role for TDP-43 in the DNA damage response.
methodsWe used NSC-34 motor neuron-like cells and primary cortical neurons expressing wildtype TDP-43 or TDP-43 ALS associated mutants (A315T, Q331K), in which DNA damage was induced by etoposide or H
resultsWe demonstrate that wildtype TDP-43 is recruited to sites of DNA damage where it participates in classical NHEJ DNA repair. However, ALS-associated TDP-43 mutants lose this activity, which induces DNA damage. Furthermore, DNA damage is present in mice displaying TDP-43 pathology, implying an active role in neurodegeneration. Additionally, DNA damage triggers features typical of TDP-43 pathology; cytoplasmic mis-localisation and stress granule formation. Similarly, inhibition of NHEJ induces TDP-43 mis-localisation to the cytoplasm.
conclusionsThis study reveals that TDP-43 functions in DNA repair, but loss of this function triggers DNA damage and is associated with key pathological features of ALS.
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