ArticleProceedings of the National Academy of Sciences of the United States of America2019
Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 205 papers, 3 of them syntheses that pooled it.
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Who cites it
205 citing papers in PubMed, 3 syntheses or guidelines pooled it, 312 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
- Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 - meta-analysis and interactive graphical database.Disease models & mechanisms · 2022Pooled it
- Article
- Innate immune crosstalk in ALS/FTD pathogenesis.Cell insight · 2026Review
- Insights into the therapeutic strategies for aging and aging-associated diseases.Signal transduction and targeted therapy · 2026Review
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Proteasomal-dependent CHK1 degradation leads to DNA damage accumulation in ALS cellular model systems.Cell death & disease · 2026Article
- RNA-binding proteins TDP-43 and FUS promote R-loop resolution and regulate transcription termination.The Journal of biological chemistry · 2026Article
- Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.bioRxiv : the preprint server for biology · 2026Article
- Calretinin and Parvalbumin Trapping of TDP43 and XRCC1 Instructs Neocortical Interneuron Death in Neonatal Hypoxic-Ischemic Encephalopathy.Biomolecules · 2026Article
- Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases.Communications biology · 2026Article
- A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms.PLoS biology · 2026Article
- Tankyrases and Their Binding Proteins: Origins of Their Roles in Diverse Cellular Pathways.Cells · 2026Review
- Microstructure and gene expression influence gyrification in amyotrophic lateral sclerosis.Brain communications · 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
- Ultraviolet radiation and neurodegeneration: molecular mechanisms underlying dual neuroprotective and neurotoxic effects.Frontiers in cellular neuroscience · 2026Review
- TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.The FEBS journal · 2026Review
- Article
- Exercise alone or combined with functional foods in aging and age-related diseases: targeting DNA damage, repair pathways, and genome integrity.Frontiers in aging neuroscience · 2026Review
145 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 7 institutions in 3 countries.
Funding
Abstract
Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in
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