TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

Topic: Brain proteins, microglia and lab models

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology. Zeng et al. show that TDP-43, known for repressing cryptic exon usage in frontotemporal dementia/amyotrophic lateral sclerosis, also controls alternative polyadenylation, impacting expression of disease-linked genes (SFPQ, NEFL and TMEM106B).

Key findings

• Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA).
• These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.

Why it matters

This study found that loss of TDP-43 from neuronal nuclei is linked to widespread changes in alternative polyadenylation, affecting disease-relevant genes such as SFPQ, NEFL and TMEM106B. It describes a new facet of TDP-43 pathology but does not test any therapy.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41593-025-02049-3
• PubMed: 41120750
• 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{zeng2025-41120750,
  author  = {Zeng, Yi and Lovchykova, Anastasiia and Akiyama, Tetsuya and Rayner, Stephanie L. and Jawahar, Vidhya Maheswari and Liu, Chang and Sianto, Odilia and Guo, Caiwei and others},
  title   = {{TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes}},
  journal = {Nature Neuroscience},
  year    = {2025},
  doi     = {10.1038/s41593-025-02049-3},
  pmid    = {41120750},
  url     = {https://doi.org/10.1038/s41593-025-02049-3}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 14.

• Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration Neurology · 2021-04-07 · usefulness score 74/100 · Long-term cohort studies
• Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions Nature genetics · 2010-02-14 · usefulness score 66/100 · Risk factors
• 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
• 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
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · 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
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• 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 loss induces cryptic polyadenylation in ALS/FTD Nature Neuroscience · 2025-10-21 · usefulness score 56/100 · Brain tissue and pathology
• TDP-43 regulates its mRNA levels through a negative feedback loop The EMBO journal · 2010-12-03 · usefulness score 51/100 · 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

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• 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
• TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD Nature Neuroscience · 2025-10-31 · usefulness score 52/100
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