ArticleThe Journal of clinical investigation2020
Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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The trial behind it
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Who cites it
90 citing papers in PubMed, 136 citations in OpenAlex.
- The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.CNS neuroscience & therapeutics · 2025Trial
- Bringing cellular clarity to the cortical component of ALS with a high-density multi-electrode array system.The FEBS journal · 2026Review
- Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD.bioRxiv : the preprint server for biology · 2026Article
- Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.Science advances · 2026Article
- The Diagnostic Potential of Axon Excitability Is Consistent Across Hand Muscles in Amyotrophic Lateral Sclerosis.Muscle & nerve · 2026Article
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2026Article
- Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.The Journal of clinical investigation · 2026Review
- ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Review
- Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.The Journal of cell biology · 2026Article
- Small molecule JRMS modulating importin-β1 chaperone activity as a therapeutic strategy reducing TDP-43 pathology.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- An autism spectrum disorder mutation in Topoisomerase 3β causes accumulation of covalent mRNA intermediates by disrupting metal binding within the zinc finger domain.Nucleic acids research · 2025Article
- Dominant-negative isoform of TDP-43 is regulated by ALS-linked RNA-binding proteins.The Journal of cell biology · 2025Article
- Skin TDP-43 pathology as a candidate biomarker for predicting amyotrophic lateral sclerosis decades prior to motor symptom onset.bioRxiv : the preprint server for biology · 2025Article
- Neuronal activity-dependent gene dysregulation inAmerican journal of physiology. Cell physiology · 2025Article
- Identifying interactions between TDP-43's N-terminal and RNA-binding domains.Protein science : a publication of the Protein Society · 2025Article
- An autism spectrum disorder mutation in Topoisomerase 3β causes accumulation of covalent mRNA intermediates by disrupting metal binding within the zinc finger domain.bioRxiv : the preprint server for biology · 2025Article
- Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.The Journal of clinical investigation · 2025Article
- Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.Life science alliance · 2025Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.