TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A
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Abstract
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.
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The most common genes identified in clinical practice include SOD1, C9ORF72, TARDBP, FUS, and OPTN/TDP-43.
“The most common genes identified in clinical practice include SOD1, C9ORF72, TARDBP, FUS, and OPTNTD-P43 (55–57, 73, 74).”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [73]
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Self-citationLoss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOsPreprint
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Gut microbiota immune cross-talk in amyotrophic lateral sclerosis
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Self-citationNuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD
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TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
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Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains
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Artificial intelligence for dementia genetics and omics
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Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder
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HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases
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Self-citationProgress in Amyotrophic Lateral Sclerosis Gene Discovery
Smukowski, S. N., Maioli, H., Latimer, C. S., Bird, T. D., Jayadev, S., & Valdmanis, P. N. (2022) · Neurology Genetics · doi:10.1212/nxg.0000000000000669 · Cited by 28 · see citing works
- Authors
- Ma, X. R., Prudencio, M., Koike, Y., Vatsavayai, S. C., Kim, G., Harbinski, F., Briner, A., Rodriguez, C. M., Guo, C., Akiyama, T., Schmidt, H. B., Cummings, B. B., Wyatt, D. W., Kurylo, K., Miller, G., Mekhoubad, S., Sallee, N., Mekonnen, G., Ganser, L., Rubien, J. D., Jansen-West, K., Cook, C. N., Pickles, S., Oskarsson, B., Graff-Radford, N. R., Boeve, B. F., Knopman, D. S., Petersen, R. C., Dickson, D. W., Shorter, J., Myong, S., Green, E. M., Seeley, W. W., Petrucelli, L., & Gitler, A. D.
- Affiliations
- Stanford Medicine (US)
- Mayo Clinic (US)
- University of California, San Francisco (US)
- Maze (United States) (US)
- The University of Queensland (AU)
- Johns Hopkins University (US)
- University of Pennsylvania (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Petrucelli, Leonard
- Gitler, Aaron D.
- ORCID
- Ma, X. Rosa
- Prudencio, Mercedes
- Koike, Yuka
- Vatsavayai, Sarat C.
- Kim, Garam
- Briner, Adam
- Rodriguez, Caitlin M.
- Guo, Caiwei
- Akiyama, Tetsuya
- Schmidt, H. Broder
- Cummings, Beryl B.
- Wyatt, David W.
- Kurylo, Katherine
- Miller, Georgiana
- Ganser, Laura
- Rubien, Jack D.
- Cook, Casey N.
- Pickles, Sarah
- Oskarsson, Björn
- Boeve, Bradley F.
- Knopman, David S.
- Petersen, Ronald C.
- Dickson, Dennis W.
- Shorter, James
- Myong, Sua
- Green, Eric M.
- Seeley, William W.
- Petrucelli, Leonard
- Gitler, Aaron D.
- Venue
- Nature
- Published
- 2022-02-23
- Volume
- 603
- Issue
- 7899
- Pages
- 124-130
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8891019
- OpenAlex
- W4213441627
- Cited by
- 574
- References
- 53
- Citations by year
- 2026: 126 · 2025: 151 · 2024: 121 · 2023: 107 · 2022: 57 · 2021: 11 · 2019: 1
- FWCI
- 57.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- ALS Association
- BrightFocus Foundation (A2020279F)
- Takeda Science Foundation
- Johns Hopkins University
- Target ALS
- Rainwater Charitable Foundation
- National Institutes of Health (W81XWH)
- University of California, San Francisco (P30AG062422, P01AG019724)
- Wu Tsai Neurosciences Institute, Stanford University
- Stanford Research Computing Center, Stanford University
- National Institute on Aging (RF1AG064690, R01AG063780, U01AG057195, U01AG006786, RF1AG071326, T32AG047126, U19AG063911, P01AG019724, P30AG062422, P30AG062677)
- National Human Genome Research Institute (T32HG000044)
- National Institute of General Medical Sciences (F32GM139268, T32GM007231)
- National Institute of Neurological Disorders and Stroke (F32NS116208, P01NS084974, R01NS104437, RF1NS120992, RF1NS113636, R35NS097273, R35NS097263, U54NS123743)
- Robert Packard Center for ALS Research, Johns Hopkins University
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- TDP-43, UNC13A, RNA splicing, amyotrophic lateral sclerosis, frontotemporal dementia, single nucleotide polymorphisms, genetic risk factors, RNA-binding proteins, motor neurons, intronic variants, induced pluripotent stem cells
- MeSH terms
- Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Exons, Humans, Motor Neurons, Nerve Tissue Proteins, Genome-Wide Association Study, Frontotemporal Dementia
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