TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A

Topic: Brain proteins, microglia and lab models

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord 1 . A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing 2-4 . Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies 5,6 , but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

Key findings

• Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies 5,6 , but how those variants increase risk for disease is unknown.
• The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction.

Why it matters

UNC13A gene variants are among the strongest genetic risk signals for FTD and ALS, but how they raise risk was unknown. In human brain tissue, neuronal cell lines and stem-cell-derived motor neurons, this study found that losing the protein TDP-43 from the nucleus lets a "cryptic exon" into UNC13A's RNA and lowers UNC13A protein, and that the top risk variants, located next to that exon, increase this mis-splicing when TDP-43 is not working. It is lab evidence linking a genetic risk factor to TDP-43 loss in FTD and ALS. It does not study Alzheimer's disease and tests no treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41586-022-04424-7
• PubMed: 35197626
• Original source →
• Free full text: Nature →

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

@article{ma2022-35197626,
  author  = {Ma, X. R. and Prudencio, M. and Koike, Y. and Vatsavayai, S. C. and Kim, G. and Harbinski, F. and Briner, A. and Rodriguez, C. M. and others},
  title   = {{TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A}},
  journal = {Nature},
  year    = {2022},
  doi     = {10.1038/s41586-022-04424-7},
  pmid    = {35197626},
  url     = {https://doi.org/10.1038/s41586-022-04424-7}
}

Studies this one cites

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

• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• 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
• 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
• 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 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proceedings of the National Academy of Sciences of the United States of America · 2009-04-21 · usefulness score 55/100 · 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
• TDP-43 regulates its mRNA levels through a negative feedback loop The EMBO journal · 2010-12-03 · usefulness score 51/100 · Lewy body dementia

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• Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing Nature Communications · 2025-04-25 · usefulness score 75/100 · Risk factors
• 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 loss induces cryptic polyadenylation in ALS/FTD Nature Neuroscience · 2025-10-21 · usefulness score 56/100 · Brain tissue and pathology
• 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-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD Nature Neuroscience · 2025-10-31 · usefulness score 52/100 · Brain tissue and pathology
• 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 · 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
• 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

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• Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases bioRxiv · 2026-09-20 · usefulness score 16/100
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