Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction

Topic: Brain proteins, microglia and lab models

Abstract TDP-43 pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report new TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7 and KCNQ2 . Using human stem cell-derived neurons, we show that TDP-43 reduction induces cryptic splicing and downregulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occur selectively in neurons with TDP-43 pathology. Importantly, suppressing individual cryptic splicing events using antisense oligonucleotides partially restores neuronal function, and combined targeting almost fully rescues the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

@article{guo2026-40949955,
  author  = {Guo, Caiwei and Chen, Kuchuan and Vatsavayai, Sarat C. and Akiyama, Tetsuya and Liu, Chang and Zeng, Yi Bo and Sianto, Odilia and Yang, Edith and others},
  title   = {{Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction}},
  journal = {Science Translational Medicine},
  year    = {2026},
  doi     = {10.1126/scitranslmed.aeb8517},
  pmid    = {40949955},
  url     = {https://doi.org/10.1126/scitranslmed.aeb8517}
}

Key findings

• Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

Why it matters

In human stem cell-derived neurons, reducing TDP-43 caused abnormal splicing and lowered levels of genes needed for nerve signaling, which impaired electrical excitability and synaptic transmission. Blocking these splicing events with antisense oligonucleotides partially restored neuronal function, and targeting several at once almost fully rescued the synaptic deficit, suggesting this process directly drives neuronal dysfunction in ALS and FTD.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1126/scitranslmed.aeb8517
• PubMed: 40949955
• Original source →
• Free full text: bioRxiv (Cold Spring Harbor Laboratory) →

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

Studies this one cites

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

• Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis Nature genetics · 2009-09-06 · usefulness score 64/100 · How common it is
• 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
• 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
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology Acta neuropathologica · 2018-12-03 · usefulness score 55/100 · Disparities

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• TDP-43: [GU]-ardian of the transcriptome Molecular Neurodegeneration · 2026-05-14 · usefulness score 42/100 · Brain tissue and pathology

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