ArticleNature neuroscience2025
TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD.
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Article in Nature neuroscience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
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Who cites it
14 citing papers in PubMed.
- Proteomic analysis reveals early pathological defects in corticospinal motor neurons of a spastin model of hereditary spastic paraplegia, which are improved by NU-9 treatment.Neurobiology of disease · 2026Article
- An upstream open reading frame represses translation of the neuronal potassium channel KCNQ2.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Regenerative strategies for ALS: stem cells and extracellular vesicles.Discover nano · 2026Review
- Article
- The Target ALS Global Natural History Study: Cross-platform proteomics to accelerate biofluid biomarker and drug target discovery in amyotrophic lateral sclerosis.medRxiv : the preprint server for health sciences · 2026Article
- Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology.Nature communications · 2026Article
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.Science (New York, N.Y.) · 2026Article
- Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.bioRxiv : the preprint server for biology · 2026Article
- Epilepsy and EEG abnormalities in neurodegenerative dementias: toward a system epilepsy framework.Frontiers in aging neuroscience · 2026Review
- Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.bioRxiv : the preprint server for biology · 2025Article
- TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD.bioRxiv : the preprint server for biology · 2025Article
- Sensitivity to TDP-43 loss and degradation resistance determine cryptic exon biomarker potential.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
37 authors.
Brian J Joseph *Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-9876-0021
Kelly A Marshall *The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID http://orcid.org/0009-0001-7936-7280
Peter Harley *UCL Queen Square Motor Neuron Disease Centre and Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0000-0001-6689-0227
Jacob R MannThe Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Francesco AlessandriniThe Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Carlos G VanoyeDepartment of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Wanhao ChiThe Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID http://orcid.org/0000-0001-6879-7018
Mercedes PrudencioDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0002-4894-4858
Dina SimkinThe Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-4473-5960
Tzu-Ting KaoDepartment of Neurology, Center for Motor Neuron Biology and Disease, Eleanor and Lou Gehrig ALS Center, Columbia University, New York, NY, USA.ORCID http://orcid.org/0009-0003-5529-7200
Reshma R DesaiDepartment of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Matthew J KeussUCL Queen Square Motor Neuron Disease Centre and Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0000-0002-2628-4115
Simone BarattucciUCL Queen Square Motor Neuron Disease Centre and Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0009-0006-8380-2931
Matteo ZanovelloUCL Queen Square Motor Neuron Disease Centre and Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
Puja R MehtaUCL Queen Square Motor Neuron Disease Centre and Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0000-0002-0255-407X
Jean-Marc DeKeyserDepartment of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Francesco LimoneDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Jonathan LeeRNA Therapeutics Institute, UMass Chan Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0001-9003-8456
Anna-Leigh BrownUCL Queen Square Motor Neuron Disease Centre and Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
Marcel F Leyton-JaimesDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-6992-8219
Leslie A NashDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Irune Guerra San JuanDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Eleonora AronicaAmsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands.ORCID http://orcid.org/0000-0002-3542-3770
Brian J WaingerDepartment of Neurology, Mass General Brigham and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-3664-7231
Mala ShahUCL School of Pharmacy, University College London, London, UK.
Anand GoswamiDepartment of Neurology, Center for Motor Neuron Biology and Disease, Eleanor and Lou Gehrig ALS Center, Columbia University, New York, NY, USA.
Neil A ShneiderDepartment of Neurology, Center for Motor Neuron Biology and Disease, Eleanor and Lou Gehrig ALS Center, Columbia University, New York, NY, USA.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID http://orcid.org/0000-0001-7189-7917
Juan BurroneCentre for Developmental Neurobiology, MRC Centre for Neurodevelopmental Disorders, Kings College London, London, UK.
Chaolin ZhangDepartments of Systems Biology, Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.ORCID http://orcid.org/0000-0002-8310-7537
Hynek WichterleDepartments of Pathology & Cell Biology, Neuroscience, and Neurology, Columbia University Irving Medical Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-7817-0080
Leonard PetrucelliDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Jonathan K WattsRNA Therapeutics Institute, UMass Chan Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0001-5706-1734
Alfred L GeorgeDepartment of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Pietro FrattaUCL Queen Square Motor Neuron Disease Centre and Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK. p.fratta@ucl.ac.uk.ORCID http://orcid.org/0000-0002-8762-8188
Kevin EgganDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Kevin.Eggan@bmrn.com.ORCID http://orcid.org/0000-0003-4436-8467
Evangelos KiskinisThe Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. evangelos.kiskinis@northwestern.edu.ORCID http://orcid.org/0000-0001-8342-8616
Funding
Project 3 - Development and investigation of murine models of channelopathy-associated epilepsyU54NS108874 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI KISKINIS, EVANGELOS · 2018 to 2022
$12.1MExpanding insights into FTD disease mechanismsR35NS097273 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2017 to 2024
$10.6MPREDOCTORAL AND POSTDOCTORAL TRAINING PROGRAM IN AGING AND DEMENTIAT32AG020506 · NIA · NORTHWESTERN UNIVERSITY AT CHICAGO · PI ROBERT J VASSAR, SANDRA WEINTRAUB · 2002 to 2026
$9.9MHuman Biomarkers CoreU54NS123743 · NINDS · STANFORD UNIVERSITY · PI FRATTA, PIETRO, GITLER, AARON D. · 2021 to 2025
$8.2MComplexity and evolution of splicing-regulatory networksR35GM145279 · NIGMS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Chaolin Zhang · 2022 to 2026
$4.6MStathmin-2 and TDP-43 neurodegeneration in Alzheimer’s and multi-etiology dementiasRF1NS120992 · NINDS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Keith A Josephs, Mercedes Prudencio · 2021 to 2026
$4.2MRNA Regulatory Networks in Neuronal Cell Type Diversity and FunctionR01NS125018 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Chaolin Zhang · 2022 to 2026
$3.0MDetermining How Defective Nucleo-Cytoplasmic Trafficking Leads To Neurodegeneration In C9orf72-Related ALS And FTDR01NS104219 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI KISKINIS, EVANGELOS · 2018 to 2022
$2.3MSyncroPatch 384 Automated Patch Clamp InstrumentS10OD034362 · OD · NORTHWESTERN UNIVERSITY · PI GEORGE, ALFRED L. · 2023 to 2023
$599kBLRD VA I01 BX002466Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R01NS125018Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R35GM145279Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R35NS097273NIA NIH HHS T32 AG020506NIGMS NIH HHS R35 GM145279NIH HHS S10 OD034362NINDS NIH HHS R01 NS104219NINDS NIH HHS R01 NS125018NINDS NIH HHS R35 NS097273NINDS NIH HHS RF1 NS120992NINDS NIH HHS U54 NS108874NINDS NIH HHS U54 NS123743U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS108874U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS104219U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) RF1NS120992U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) U54NS123743Wellcome Trust
Abstract
Motor neuron hyperexcitability is a broadly observed yet poorly understood feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear depletion and cytoplasmic aggregation of the RNA splicing protein TAR DNA-binding protein 43 (TDP-43) are observed in most ALS and FTD patients. Here we show that TDP-43 dysfunction causes mis-splicing of KCNQ2, which encodes a voltage-gated potassium channel (K
Indexed as
Amyotrophic Lateral SclerosisDNA-Binding ProteinsFrontotemporal DementiaKCNQ2 Potassium ChannelMotor NeuronsRNA SplicingAnimalsFemaleHumansInduced Pluripotent Stem CellsMaleNeuronsDNA-Binding ProteinsKCNQ2 Potassium ChannelKCNQ2 protein, humanTARDBP protein, human
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