ArticleScience translational medicine2024
Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.
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Article in Science translational medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 1 of them a synthesis that pooled it.
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130citing papers in PubMed, 1 pooled it
55.4field-weighted citation impact, top 1% of its field
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Who cites it
130 citing papers in PubMed, 1 synthesis or guideline pooled it, 139 citations in OpenAlex.
- Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Pooled it
- TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD.bioRxiv : the preprint server for biology · 2026Article
- Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS.Research square · 2026Article
- Review
- MARBLE: An in vivo MRI marker of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC).Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.Alzheimer's research & therapy · 2026Article
- TDP-43 controls RNA structure through high affinity lattice interactions.Nature communications · 2026Article
- Article
- TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.Biochemical Society transactions · 2026Review
- TDP-43 dysfunction facilitates the pathological conversion of tau.Molecular neurodegeneration · 2026Article
- Biochemical and Immunohistochemical Associations of TDP-43 and Cryptic RNA With Hippocampal and Amygdala Volumetrics in Alzheimer's Disease.Annals of neurology · 2026Article
- Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.Nature neuroscience · 2026Article
- 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
- Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression.The Journal of clinical investigation · 2026Article
- TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.Neurochemical research · 2026Review
- Molecular signatures and biomarker development for limbic-predominant age-related TDP-43 encephalopathy (LATE).Acta neuropathologica · 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
- Augmented prediction of multi-species protein-RNA interactions using evolutionary conservation of RNA-binding proteins.Nature communications · 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
70 more citing papers are in PubMed but not listed here.
Corrections and comments
- Update of
Authors and funding
51 authors at 9 institutions in 3 countries.
Sahba SeddighiNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0003-1920-2828
Yue A QiCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0003-1914-8710
Anna-Leigh BrownUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0003-1493-208X
Oscar G WilkinsUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0002-3334-0568
Colleen BeredaCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-9435-6141
Cedric BelairLaboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.ORCID 0000-0003-4007-2060
Yong-Jie ZhangDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0002-9900-4313
Mercedes PrudencioDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0002-4894-4858
Matthew J KeussUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0002-2628-4115
Aditya KhandeshiLaboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.ORCID 0009-0004-8541-1702
Sarah PicklesDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0001-7956-4586
Sarah E Kargbo-HillNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-8499-7455
James HawrotNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0001-8050-8274
Daniel M RamosCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-4041-5273
Hebao YuanNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0003-4425-3678
Jessica RobertsCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0009-0001-4103-9222
Erika Kelmer SacramentoLeibniz Institute on Aging, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.ORCID 0000-0002-3336-982X
Syed I ShahData Tecnica International, Washington, DC, USA.ORCID 0000-0002-2094-3386
Mike A NallsCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Jennifer M Colón-MercadoNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-2912-554X
Joel F ReyesNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-2354-4874
Veronica H RyanNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0001-5121-4672
Matthew P NelsonCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Casey N CookDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0002-5963-8442
Ziyi LiCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-5165-8772
Laurel ScrevenCenter for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0009-0007-8630-6754
Justin Y KwanNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Puja R MehtaUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0002-0255-407X
Matteo ZanovelloUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0003-3343-1547
Martina HalleggerFrancis Crick Institute, London, UK.ORCID 0000-0002-5126-5346
Anantharaman ShantaramanDepartment of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.ORCID 0000-0003-1384-941X
Lingyan PingDepartment of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.ORCID 0000-0002-2623-5145
Yuka KoikeDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0002-5067-8579
Björn OskarssonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0002-1725-9866
Nathan P StaffDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.ORCID 0000-0001-6760-3859
Duc M DuongDepartment of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.ORCID 0000-0001-5880-1888
Aisha AhmedUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0001-6928-4775
Maria SecrierDepartment of Genetics, Evolution and Environment, UCL Genetics Institute, UCL, London, UK.ORCID 0000-0003-2758-1741
Jernej UleFrancis Crick Institute, London, UK.ORCID 0000-0002-2452-4277
Steven JacobsonNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0003-3127-1287
Daniel S ReichNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-2628-4334
Jonathan D RohrerUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0002-6155-8417
Andrea MalaspinaUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0001-7189-7917
Jonathan D GlassDepartment of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA.ORCID 0000-0002-3295-4971
Alessandro OriLeibniz Institute on Aging, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
Nicholas T SeyfriedDepartment of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.ORCID 0000-0002-8694-9211
Manolis MaragkakisLaboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.ORCID 0000-0002-3158-1763
Leonard PetrucelliDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.ORCID 0000-0003-2959-129X
Pietro FrattaUCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK.ORCID 0000-0002-8762-8188
Michael E WardNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0002-5296-8051
National Institutes of Health · USJacksonville College · USNational Hospital for Neurology and Neurosurgery · GBEmory University · USKing's College London · GBLeibniz Institute on Aging - Fritz Lipmann Institute (FLI) · DEThe Francis Crick Institute · GBInstitute of Genetics and Cancer · GBMayo Clinic in Arizona · US
Funding
Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI ADAM L. BOXER, Bradley F Boeve · 2019 to 2026
$120.9MMultimodal MRI in Multiple SclerosisZIANS003119 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI REICH, DANIEL · 2010 to 2025
$53.4MResearch Education ComponentP30AG062677 · NIA · MAYO CLINIC ROCHESTER · PI NILUFER ERTEKIN-TANER · 2019 to 2026
$33.5MMechanisms of inherited neurodegenerative diseasesZIANS003155 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI WARD, MICHAEL · 2016 to 2025
$24.7MProject 3: Neuropathology of the multi-proteinopathy of c9FTD/ALS.P01NS084974 · NINDS · MAYO CLINIC JACKSONVILLE · PI FRYER, JOHN DAVID · 2014 to 2024
$17.6MRNA dynamics and co-translational decay in aging and aging-related diseaseZIAAG000696 · NIA · NATIONAL INSTITUTE ON AGING · PI MARAGKAKIS, MANOLIS · 2020 to 2025
$14.0MMedical Scientist Training ProgramT32GM136577 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI ANDREA L COX · 2020 to 2026
$13.4MExpanding insights into FTD disease mechanismsR35NS097273 · NINDS · MAYO CLINIC JACKSONVILLE · PI PETRUCELLI, LEONARD · 2017 to 2024
$10.6MHuman Biomarkers CoreU54NS123743 · NINDS · STANFORD UNIVERSITY · PI GITLER, AARON D. · 2021 to 2025
$8.2MNovel genetic modifiers of C9orf72 and Tau toxicityRF1AG062077 · NIA · MAYO CLINIC ARIZONA · PI FRYER, JOHN DAVID, PETRUCELLI, LEONARD · 2019 to 2019
$4.0MNuclear Pore Complex and as a Contributor to Tau Associated DementiaRF1AG062171 · NIA · JOHNS HOPKINS UNIVERSITY · PI PETRUCELLI, LEONARD, ROTHSTEIN, JEFFREY D · 2019 to 2019
$3.8MThe role of neuronal mRNA transport granule packaging in ALS/FTDFI2GM142475 · NIGMS · U.S. NATIONAL INST/NEURO/DS/STROKE · PI RYAN, VERONICA HANLEY · 2021 to 2021
–Intramural NIH HHS ZIA NS003155Medical Research Council MC_PC_MR/S022708/1Medical Research Council MR/J009482/1Medical Research Council MR/M008525/1Medical Research Council MR/M023664/1Medical Research Council MR/S006508/1Medical Research Council MR/T046015/1Medical Research Council MR/W005190/1Motor Neurone Disease Association HALLEGGER/OCT15/959-799Motor Neurone Disease Association MALASPINA/APR13/817-791NIA NIH HHS P30 AG062677NIA NIH HHS RF1 AG062077NIA NIH HHS RF1 AG062171NIA NIH HHS U19 AG063911NIGMS NIH HHS FI2 GM142475NIGMS NIH HHS T32 GM136577NINDS NIH HHS P01 NS084974NINDS NIH HHS R35 NS097273NINDS NIH HHS U54 NS123743Wellcome Trust CC0102
Abstract
Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.
Indexed as
Amyotrophic Lateral SclerosisFrontotemporal DementiaDNA-Binding ProteinsHumansPeptidesProteomicsDNA-Binding ProteinsPeptidesTARDBP protein, human
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