TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Topic: Brain proteins, microglia and lab models

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia 1-3 , two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43 4,5 . Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Key findings

• Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites.
• Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function.

Why it matters

TDP-43 depletion causes a cryptic exon to be included in UNC13A, leading to loss of UNC13A protein, and common risk variants overlap with TDP-43 binding sites and worsen this. The authors call this a promising therapeutic target, but no treatment has been tested.

Study details

• Evidence strengthLow

Limitations

This is a laboratory molecular-biology study of gene splicing mechanisms; it does not itself test or demonstrate this mechanism in patients, so its clinical relevance depends on future work.

Read the original

• DOI: 10.1038/s41586-022-04436-3
• PubMed: 35197628
• 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{brown2022-35197628,
  author  = {Brown, A. L. and Wilkins, O. G. and Keuss, M. J. and Kargbo-Hill, S. E. and Zanovello, M. and Lee, W. C. and Bampton, A. and Lee, F. C. Y. and others},
  title   = {{TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A}},
  journal = {Nature},
  year    = {2022},
  doi     = {10.1038/s41586-022-04436-3},
  pmid    = {35197628},
  url     = {https://doi.org/10.1038/s41586-022-04436-3}
}

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 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families Science · 1993-08-13 · usefulness score 63/100 · Genetics
• 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

Later studies that cite this one

24 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• 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

Related studies in Lewy body dementia

• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100
• Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo Human molecular genetics · 2009-12-03 · usefulness score 50/100
• Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery Journal of proteome research · 2010-02-01 · usefulness score 47/100
• Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits Science (New York, N.Y.) · 2015-05-14 · usefulness score 57/100
• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100
• Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases bioRxiv · 2026-09-20 · usefulness score 16/100

Similar studies

• Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD 2024 · Brain tissue and pathology
• Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice 2011 · Lewy body dementia
• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis 2019 · Lewy body dementia
• Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations 2014 · Lewy body dementia
• TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets 2015 · Brain tissue and pathology
• Understanding the role of TDP-43 and FUS/TLS in ALS and beyond 2011 · Brain tissue and pathology

More on Lewy body dementia

• A review that covers this ground The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism Proceedings of the National Academy of Sciences of the United States of America · 2006-12-29 · usefulness score 49/100
• Newest in this subject Frequency-Resolved Connectivity Graphs for EEG-Based Classification of Alzheimer and Frontotemporal Dementia bioRxiv · 2026-10-22 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Dementia and PDE5 inhibitors: A retrospective cohort study of veterans Research Square · 2026-10-13 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Lewy body dementia →