ArticleNature neuroscience2025
Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification.
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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 41 papers, 1 of them a synthesis that pooled it.
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41citing papers in PubMed, 1 pooled it
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Bibliometric analysis of RNA-binding proteins in osteosarcoma: unraveling research trends and hotspots.Frontiers in immunology · 2025Pooled it
- Multiple motor proteins regulate TDP-43 anterograde axonal transport.Acta neuropathologica · 2026Article
- Expanded Polyglycine Protein Aggregates Alter the RNA Splicing Profile into a Premature State Partially via Sequestering SF3B4.Neuroscience bulletin · 2026Article
- Distinct single-nucleus RNA-seq changes among non-neuronal cells in ADNC, LATE-NC, and mixed pathologies.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- mNature reviews. Neuroscience · 2026Review
- Human-specific sequence features in HTT exon 1 promote toxic misprocessing via splicing factor SRSF7.Nature communications · 2026Article
- ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid-β Pathology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Data-driven model reveals increased stability of CAG-expanded huntingtin RNA due to MID1 binding.PLoS computational biology · 2026Article
- FTO-modulated mJournal of translational medicine · 2026Article
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- m6A deficiency induces dopaminergic neurodegeneration and progressive parkinsonism through a pathogenic loop with mitochondria.The Journal of clinical investigation · 2026Article
- Integrated m6A methylome and transcriptome profiling of mRNAs and lncRNAs in nasal mucosal epithelial cells of allergic rhinitis patients undergoing allergen-specific immunotherapy.Clinical epigenetics · 2026Article
- FTO-mediated mActa pharmaceutica Sinica. B · 2026Article
- m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.Molecular brain · 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
- Mettl3-mediated m6A disruption of olfactory bulb glutamatergic metabolism homeostasis via the Wnt pathway in aging leads to olfactory dysfunction.Cellular and molecular life sciences : CMLS · 2026Article
- Exon skipping as a potential diagnostic biomarker in colorectal cancer: an integrated epigenomic-transcriptomic analysis.Human genomics · 2026Article
- Global research architecture of RNA-binding proteins in neurodegenerative diseases: a web of science bibliometric study with PubMed record verification, 2001-2025.Frontiers in aging neuroscience · 2026Article
- Aberrant NSUN1 activity connects mLife science alliance · 2026Article
- Revisiting the clastosome: a stress-induced nuclear proteolytic compartment of mammalian cells.Frontiers in neuroanatomy · 2026Review
Corrections and comments
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Authors and funding
29 authors.
Thai B NguyenDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Ricardo MiramontesUCI MIND, University of California, Irvine, Irvine, CA, USA.
Carlos Chillon-MarinasDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Roy MaimonDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Sonia Vazquez-SanchezDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Alice L LauDepartment of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA, USA.
Nicolette R McClureDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Zhuoxing WuDepartment of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Keona Q WangDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.ORCID http://orcid.org/0000-0002-7715-2489
Whitney E EnglandDepartment of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
Monika SinghaDepartment of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
Jennifer T StocksdaleDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Marie HeathDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Ki-Hong JangDepartment of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Sunhee JungDepartment of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Karen LingIonis Pharmaceuticals, Inc., Carlsbad, CA, USA.ORCID http://orcid.org/0000-0002-5895-6684
Paymann Jafar-NejadIonis Pharmaceuticals, Inc., Carlsbad, CA, USA.
Jharrayne I McKnightDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Leanne N HoDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
Osama Al DalahmahDepartment of Pathology and Cell Biology, Columbia University, New York, NY, USA.ORCID http://orcid.org/0000-0002-3442-5459
Richard L M FaullDepartment of Anatomy and Medical Imaging, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand.
Joan S SteffanDepartment of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA, USA.ORCID http://orcid.org/0000-0003-2467-6294
Jack C ReidlingUCI MIND, University of California, Irvine, Irvine, CA, USA.
Cholsoon JangDepartment of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.ORCID http://orcid.org/0000-0001-6651-4213
Gina LeeDepartment of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Don W ClevelandDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-1934-3682
Clotilde Lagier-TourenneDepartment of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-3058-8322
Robert C SpitaleDepartment of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA. rspitale@uci.edu.ORCID http://orcid.org/0000-0002-3511-8098
Leslie M ThompsonDepartment of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.ORCID http://orcid.org/0000-0003-4573-9514
Funding
NEURONAL FILAMENT SYNTHESIS, ASSEMBLY, AND FUNCTIONR01NS027036 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Bogdan Bintu, Don W Cleveland · 1989 to 2026
$11.8MMolecular Mechanisms of Pathogenesis in Huntington’s diseaseR35NS116872 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI Leslie Michels Thompson · 2020 to 2026
$8.5MDetermining stathmin-2 function and potential as a therapeutic target in ALS/FTDR01NS112503 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CLEVELAND, DON W, LAGIER-TOURENNE, CLOTILDE · 2020 to 2024
$4.1MNeurofilaments, SOD1 and Motor Neuron DiseasesR37NS027036 · NINDS · LUDWIG INSTITUTE FOR CANCER RES LTD · PI CLEVELAND, DON W · 2005 to 2011
$4.1MMechanism of stathmin-2-dependent axon maintenance, regeneration, and functionR37NS112503 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CLEVELAND, DON W, LAGIER-TOURENNE, CLOTILDE · 2025 to 2025
$3.1MIn vivo modelling and therapy development for stathmin-2 loss in TDP-43 proteinopathiesRF1NS124203 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI CLEVELAND, DON W, LAGIER-TOURENNE, CLOTILDE · 2021 to 2021
$2.5MElucidating dietary fructose and alcohol interactions during liver cancer developmentR01AA029124 · NIAAA · UNIVERSITY OF CALIFORNIA-IRVINE · PI JANG, CHOLSOON · 2021 to 2025
$2.0MIn vivo modelling and therapy development for stathmin-2 loss in TDP-43 proteinopathiesR01NS124203 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI CLEVELAND, DON W, LAGIER-TOURENNE, CLOTILDE · 2024 to 2025
$1.6MElucidating the regulation of RNA methylation by mTOR signaling in cancerK22CA234399 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI LEE, GINA · 2022 to 2023
$440kFunctional impact of N6-Methyadenosine (m6A) modification in Huntington's diseaseF31NS124293 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI NGUYEN, THAI BAO NGO · 2022 to 2022
$37kNCI NIH HHS K22 CA234399NIAAA NIH HHS R01 AA029124NINDS NIH HHS F31 NS124293NINDS NIH HHS R01 NS027036NINDS NIH HHS R01 NS112503NINDS NIH HHS R01 NS124203NINDS NIH HHS R35 NS116872NINDS NIH HHS R37 NS027036NINDS NIH HHS R37 NS112503NINDS NIH HHS RF1 NS124203U.S. Department of Defense (United States Department of Defense) TS200022U.S. Department of Health & Human Services | National Institutes of Health (NIH) AA029124U.S. Department of Health & Human Services | National Institutes of Health (NIH) F31NS124293T32U.S. Department of Health & Human Services | National Institutes of Health (NIH) K22CA234399U.S. Department of Health & Human Services | National Institutes of Health (NIH) NS112503U.S. Department of Health & Human Services | National Institutes of Health (NIH) NS116872U.S. Department of Health & Human Services | National Institutes of Health (NIH) NS124203U.S. Department of Health & Human Services | National Institutes of Health (NIH) NS27036
Abstract
Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Disrupted nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 occurs in HD mouse and human brains, with TDP-43 also co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum of HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD.
Indexed as
AdenosineAlternative SplicingDNA-Binding ProteinsHuntington DiseaseRNA SplicingAnimalsBrainHumansHuntingtin ProteinMaleMethyltransferasesMiceMice, TransgenicRNA MethylationAdenosineDNA-Binding ProteinsHTT protein, humanHuntingtin ProteinMethyltransferasesMETTL3 protein, humanMettl3 protein, mouseN-methyladenosineTARDBP protein, humanTardbp protein, mouse
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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 Socratic graph.