TDP-43 loss induces cryptic polyadenylation in ALS/FTD

Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3' untranslated region (3'UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3'UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43.

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Publication Details

Journal
Nature Neuroscience
Published
2025-10-21
DOI
https://doi.org/10.1038/s41593-025-02050-w
Citations
13
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
18.06

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article

TDP-43 loss induces cryptic polyadenylation in ALS/FTD

Avindra Nath, Puja R. Mehta, Jack Humphrey, Anna‐Leigh Brown et al.
13 citations
Nature Neuroscience
Amyotrophic Lateral Sclerosis Research
18.06
article

TDP-43 loss induces cryptic polyadenylation in ALS/FTD

Avindra Nath, Puja R. Mehta, Jack Humphrey, Anna‐Leigh Brown, Eleonora Aronica, Terry Heiman‐Patterson, Eli A. Stahl, Kerstin Lindblad‐Toh, William J. Salerno, Oleg Butovsky, Matteo Zanovello, Sarah E. Hill, Vilas Menon, Stephen Muljo, Lani F. Wu, Matt Brauer, Sabrina Paganoni, Shameek Biswas, Efthimios Dardiotis, Timothy M. Miller, Brent T. Harris, Suma Babu, Michael Emmerson Ward, Dhruv Sareen, Jose Norberto S. Vargas, Kendall R. Van Keuren‐Jensen, Molly Hammell, Frank Baas, Zachary Simmons, Sam Bryce-Smith, Bin Zhang, Bryan J. Traynor, James D. Berry, Sulev Kõks, Marc Gotkine, Corey T. McMillan, Yue Qi, Mickey Atwal, James R. Broach, Eran Hornstein, Vivianna M. Van Deerlin, Leslie Michels Thompson, Ximena Arcila-Londono, Ernest Fraenkel, David A. Frendewey, Hemali Phatnani, Darius J. Adams, Dario Dattilo, Towfique Raj, Daphne Koller, Kimberly Wilson, Dale J. Lange, Robert Bowser, Michael Cantor, Nazem Atassi, Noah Zaitlen, Thomas G. Blanchard, Flaminia Pellegrini, Edward B. Lee, Nicol Birsa, T. Nickerson, Gregory A. Cox, Andrea Malaspina, Simone Barattucci, Steven M. Finkbeiner, Nikolaos A. Patsopoulos, Yixuan Wan, John F. Crary, Alla Mikheenko, Josh Dubnau, Colin Smith, Matthew J. Keuss, Jennifer E. Phillips‐Cremins, Orit Rozenblatt–Rosen, Steven J. Altschuler, Ophir Shalem, Neil A. Shneider, Robert Moccia, Mary Poss, Peter K. Gregersen, Lyle W. Ostrow, Katharine Nicholson, John Ravits, Rita Sattler, Oscar G. Wilkins, Robert H. Baloh, Francesca Mattedi, Sara Emad El-Agamy, Daniel J. L. MacGowan, Max Z. Y. J. Chien, Iris Broce, Leonidas Stefanis, Suvankar Pal, Eugeni Ryadnov, Matthew Yome, Jeong‐Ho Lee, Matt Anderson, Siddharthan Chandran, Justin Kwan, Maria Secrier, Pietro Fratta, Seng H. Cheng, Andrew Deubler, Giovanni Coppola, Vivian E. Drory, Matthew B. Harms, Yossef Lerner, Kai Sun, Mary Rozenman
article en
13 citations

Abstract

Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3' untranslated region (3'UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3'UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43.

Nature NeuroscienceVol. 28(11)
Broad Institute (US), University of Maryland, Baltimore (US), Hospital for Special Surgery (US), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), Mott MacDonald (United Kingdom) (GB), Translational Genomics Research Institute (US), National Institutes of Health (US), Northwell Health (US), Pennsylvania State University (US), Allen Institute for Brain Science (US), Gladstone Institutes (US), Barrow Neurological Institute (US), St. Joseph's Hospital and Medical Center (US), Feinstein Institute for Medical Research (US), Children's Hospital of Philadelphia (US), Harvard University (US), Johns Hopkins University (US), University of Thessaly (GR), Henry Ford Health System (US), Korea Advanced Institute of Science and Technology (KR), Tel Aviv University (IL), Queen Mary University of London (GB), University of California, San Francisco (US), Pfizer (United States) (US), Georgetown University (US), Regeneron (United States) (US), Hebrew University of Jerusalem (IL), National and Kapodistrian University of Athens (GR), University of California, Irvine (US), Washington University in St. Louis (US), Cornell University (US), Cold Spring Harbor Laboratory (US), Columbia University Irving Medical Center (US), Spaulding Rehabilitation Hospital (US), Tel Aviv Sourasky Medical Center (IL), Johns Hopkins Medicine (US), Hadassah Medical Center (IL), Georgetown University Medical Center (US), Leiden University Medical Center (NL), Overlook Medical Center (US), The Francis Crick Institute (GB), New York Stem Cell Foundation (US), Morristown Medical Center (US), Amsterdam UMC Location University of Amsterdam (NL), University of California San Diego (US), Massachusetts General Hospital (US), Clinical Research Institute (US), Bristol-Myers Squibb (United States) (US), Biomedical Research Foundation of the Academy of Athens (GR), MRC Centre for Regenerative Medicine (GB), National Institute of Neurological Disorders and Stroke (US), Jackson Laboratory (US), Maze (United States) (US), Basildon Hospital (GB), National Institute of Allergy and Infectious Diseases (US), National Institute on Aging (US), Eginition Hospital (GR), Perron Institute for Neurological and Translational Science (AU), Institute of Aging (CA), New York Genome Center (US), Taube Koret Center (US), Institute of Genetics (HU), University College London (GB), Weizmann Institute of Science (IL), Stony Brook University (US), Massachusetts Institute of Technology (US), Atlantic Health System (US), Columbia University (US), University of Pennsylvania (US), Temple University (US), University of Amsterdam (NL), University of Edinburgh (GB), Icahn School of Medicine at Mount Sinai (US)
Wellcome Trust, Francis Crick Institute, Target ALS, Brain Research UK, Cancer Research UK, Motor Neurone Disease Association, Rosetrees Trust, National Institutes of Health, Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 1%
Amyotrophic Lateral Sclerosis Research
18.06
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