Evidence map›Paper›PMID 39792557›Full record

ArticleCell reports2025

TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.

Megan M Dykstra, Kaitlin Weskamp, Nicolás B Gómez, Jacob Waksmacki, Elizabeth Tank, M Rebecca Glineburg, Allison Snyder, Emile Pinarbasi, Michael Bekier, Xingli Li and 16 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

  1. Article
  2. TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026
    Review
  3. Review
  4. Review
  5. 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 · 2026
    Article
  6. Article
  7. Article
  8. Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD.bioRxiv : the preprint server for biology · 2025
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

26 authors.

Megan M DykstraNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Kaitlin WeskampChemistry Department, Nebraska Wesleyan University, Lincoln, NE, USA.
Nicolás B GómezGraduate Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
Jacob WaksmackiDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
Elizabeth TankDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
M Rebecca GlineburgBiological Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA, USA.
Allison SnyderNeurogenetics Branch, NINDS, NIH, Bethesda, MD, USA.
Emile PinarbasiDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA; Neuropathology, Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
Michael BekierDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
Xingli LiDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
Morgan R MillerNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Jen BaiDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
Shameena ShahzadDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
Neha NedumaranDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
Clare WielandNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
Corey StewartNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Sydney WilleyNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Nikolas GrotewoldMedical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
Jonathon McBrideDepartment of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
John J MoranAtlanta Pediatric Research Alliance, Emory University, Atlanta, GA, USA.
Aditya V SuryakumarDepartment of Neurology, University of Michigan, Ann Arbor, MI, USA.
Michael LucasDepartments of Chemical Engineering and Pharmaceutical Sciences, Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
Peter M TessierDepartments of Chemical Engineering and Pharmaceutical Sciences, Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
Michael WardNeurogenetics Branch, NINDS, NIH, Bethesda, MD, USA.
Peter K ToddNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Veterans Affairs Medical Center, Ann Arbor, MI, USA.
Sami J BarmadaNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA. Electronic address: sbarmada@umich.edu.

Funding

MICHIGAN MEDICAL SCIENTIST TRAINING PROGRAMT32GM007863 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI COLLINS, KATHLEEN L. · 1985 to 2024
$38.3M
Research Education ComponentP30AG072931 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Henry L Paulson · 2021 to 2026
$26.5M
Hexanucleotide repeat translation in ALS and Frontotemporal DementiaR01NS099280 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Peter K Todd · 2016 to 2026
$4.9M
Cellular and Molecular Biology at MichiganT32GM145470 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI John Chadwick Brenner · 2022 to 2026
$4.1M
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degenerationR01NS097542 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BARMADA, SAMI · 2016 to 2025
$3.8M
Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALSR01NS113943 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BARMADA, SAMI · 2020 to 2024
$1.9M
Structure-guided antibody targeting of pre-selected epitopes in amyloidogenic aggregatesR35GM136300 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TESSIER, PETER M · 2020 to 2024
$1.5M
Elucidating the Mechanisms Underlying Mutant TDP43-induced NeurodegenerationK08NS072233 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BARMADA, SAMI · 2011 to 2015
$879k
Spatiotemporal analysis of TDP-43 toxicity and endolysosomal turnover mechanismsR56NS128110 · NINDS · UNIVERSITY OF ARIZONA · PI BARMADA, SAMI, BUCHAN, JOHN ROSS · 2022 to 2022
$393k
Identifying the function of alternatively spliced TDP43 isoforms and contribution to diseaseF31NS134123 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI DYKSTRA, MEGAN · 2023 to 2024
$83k
Investigating the mechanism of UPF1-mediated rescue of TDP-43-based models of ALS and FTDF31NS115257 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GOMEZ, NICOLAS BENJAMIN · 2019 to 2021
$76k
BLRD VA I01 BX004842NIA NIH HHS P30 AG072931NIGMS NIH HHS R35 GM136300NIGMS NIH HHS T32 GM007863NIGMS NIH HHS T32 GM145470NINDS NIH HHS F31 NS115257NINDS NIH HHS F31 NS134123NINDS NIH HHS K08 NS072233NINDS NIH HHS R01 NS097542NINDS NIH HHS R01 NS099280NINDS NIH HHS R01 NS113943NINDS NIH HHS R56 NS128110
6 · The paper itself

Abstract

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and underscore the consequences of aberrant sTDP43 accumulation in disease.

Indexed as

DNA-Binding ProteinsHomeostasisProtein Processing, Post-TranslationalTranscription, GeneticAnimalsHEK293 CellsHumansMiceNonsense Mediated mRNA DecayProtein IsoformsDNA-Binding ProteinsProtein IsoformsTARDBP protein, humanALSCP: Molecular biologyCP: Neurosciencecryptic splicingFTLD-TDPneurodegenerationnonsense-mediated RNA decayTDP43

Identifiers

PMID39792557
PMCPMC11848802

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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.