ArticleActa neuropathologica2019
Splicing repression is a major function of TDP-43 in motor neurons.
Article in Acta neuropathologica, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 100 citations in OpenAlex.
- Functional Activity of TDP-43: A Direct Biomarker for ALS.Biosensors · 2026Article
- Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.Journal of neurology · 2026Review
- TDP-43 dysfunction facilitates the pathological conversion of tau.Molecular neurodegeneration · 2026Article
- Article
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Aberrant Splicing Signatures Underpin Oligodendrocyte Damage in ALS and Neuron Loss in FTD.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study.Annals of neurology · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- From development to disease: the neuronal role of hnRNPs through the lens ofFrontiers in cell and developmental biology · 2026Review
- Aberrant NSUN1 activity connects mLife science alliance · 2026Article
- Single-nucleus RNA sequencing reveals GABAergic vulnerability and reactive gliosis driven by loss of TDP-43.iScience · 2025Article
- Broad brain biodistribution conferred by an AAV to restore TDP-43 function mitigates Frontotemporal Demenia-like deficits.bioRxiv : the preprint server for biology · 2025Article
- TDP-43 binds to RNA G-quadruplex structure and regulates mRNA stability and translation.Nucleic acids research · 2025Article
- Symptomatic treatment by a BBB-permeable AAV engineered to restore TDP-43 function slows motor neuron disease and prevents paralysis.bioRxiv : the preprint server for biology · 2025Article
- Article
- Inhibition of nonsense-mediated decay in TDP-43 deficient neurons reveals novel cryptic exons.bioRxiv : the preprint server for biology · 2025Article
- Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing.Acta neuropathologica · 2025Article
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- Challenges of modelling TDP-43 pathology in mice.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Loss of TDP-43 Splicing Repression Occurs in Myonuclei of Inclusion Body Myositis Patients.Annals of neurology · 2025Article
9 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Nuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression in Drosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.
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Registered trials
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.