TDP-43 loss induces cryptic polyadenylation in ALS/FTD

Topic: Brain proteins, microglia and lab models

Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3' untranslated region (3'UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3'UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43.

Key findings

• RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3'UTR extensions can increase RNA stability, leading to increased translation.

Why it matters

This laboratory study found that loss of TDP-43 in stem cell-derived neurons causes cryptic alternative polyadenylation events, which were also seen in ALS and frontotemporal dementia brain tissue. It identifies a newly described consequence of TDP-43 loss but does not test any treatment, prevention or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41593-025-02050-w
• PubMed: 41120751
• Original source →
• Free full text: Nature Neuroscience →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{brycesmith2025-41120751,
  author  = {Bryce-Smith, Sam and Brown, Anna‐Leigh and Chien, Max Z. Y. J. and Dattilo, Dario and Mehta, Puja R. and Mattedi, Francesca and Barattucci, Simone and Mikheenko, Alla and others},
  title   = {{TDP-43 loss induces cryptic polyadenylation in ALS/FTD}},
  journal = {Nature Neuroscience},
  year    = {2025},
  doi     = {10.1038/s41593-025-02050-w},
  pmid    = {41120751},
  url     = {https://doi.org/10.1038/s41593-025-02050-w}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · Lewy body dementia
• Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies Science (New York, N.Y.) · 2023-03-16 · usefulness score 60/100 · Brain tissue and pathology
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia
• Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia The Journal of clinical investigation · 2020-11-01 · usefulness score 57/100 · Brain tissue and pathology
• TDP-43 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · usefulness score 56/100 · Lewy body dementia
• TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes Nature Neuroscience · 2025-10-21 · usefulness score 55/100 · Brain tissue and pathology
• TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia Journal of Clinical Investigation · 2025-06-01 · usefulness score 51/100 · Lewy body dementia
• Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins Journal of neurochemistry · 2016-06-15 · usefulness score 49/100 · Lewy body dementia

Later studies that cite this one

4 studies in the alzhub library list this one in their references. Showing the 3 highest-scoring.

• TDP-43-mediated alternative polyadenylation is associated with a reduction in VPS35 and VPS29 expression in frontotemporal dementia PLoS Biology · 2026-01-05 · usefulness score 48/100 · Lewy body dementia
• DCPS modulates TDP-43-linked neurodegeneration through P-body-mediated RNA decay Neuron · 2026-03-09 · usefulness score 45/100 · Brain tissue and pathology
• TDP-43: [GU]-ardian of the transcriptome Molecular Neurodegeneration · 2026-05-14 · usefulness score 42/100 · Brain tissue and pathology

Related studies in Brain tissue and pathology

• Quantifying subpercent nuclear TDP ‐43 loss in cells and ALS cortex using junction‐specific cryptic exon RT ‐ qPCR FEBS Letters · 2025-10-22 · usefulness score 35/100
• Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures Neuron · 2025-03-31 · usefulness score 35/100
• Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction Science Translational Medicine · 2026-06-03 · usefulness score 51/100
• TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nature neuroscience · 2018-03-19 · usefulness score 56/100
• ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43 Nature communications · 2014-06-03 · usefulness score 55/100
• Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD Neuron · 2019-07-01 · usefulness score 52/100

Also tagged “mice”

1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Dendritic spines provide cognitive resilience against Alzheimer's disease Annals of neurology · 2017-10-22 · usefulness score 48/100 · Digital health tools
• Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons Nature neuroscience · 2013-09-15 · usefulness score 55/100 · Lewy body dementia

Similar studies

• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 2013 · Lewy body dementia
• TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord 2025 · Brain tissue and pathology
• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD 2018 · Lewy body dementia
• Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis 2010 · Lewy body dementia
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• TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets 2015 · Brain tissue and pathology

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• A review that covers this ground FTD and ALS: a tale of two diseases Current Alzheimer research · 2011-05-01 · usefulness score 41/100
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