TDP-43 loss induces cryptic polyadenylation in ALS/FTD

Journal article

Sam Bryce-Smith, Anna-Leigh Brown, Max Z. Y. J. Chien, Dario Dattilo, Puja R. Mehta, F. Mattedi, Simone Barattucci, A. Mikheenko, M. Zanovello, F. Pellegrini, Sara Emad El-Agamy, Matthew Yome, Sarah E Hill, Y. A. Qi, Kai Sun, Eugeni Ryadnov, Yixuan Wan, Hemali Justin Dhruv James R. Zachary Ximena Edward B. Viv Phatnani Kwan Sareen Broach Simmons Arcila-Londono, Hemali Phatnani, Justin Kwan, D. Sareen, James R Broach, Zachary Simmons, Ximena Arcila-Londono, Edward B Lee, V. V. Van Deerlin, Neil A. Shneider, Ernest Fraenkel, L. Ostrow, Frank Baas, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, S. Pal, E. Hornstein, D. MacGowan, Terry Heiman-Patterson, M. Hammell, N. Patsopoulos, Joshua Dubnau, Avindra Nath, R. Bowser, Matthew M Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, N. Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, M. Gotkine, Robert H. Baloh, Suma Babu, S. Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Justin Kwan, Thomas Blanchard, Brent Harris, Iris J. Broce, V. Drory, J. Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steve Altschuler, Y. Lerner, Rita Sattler, K. Van Keuren-Jensen, O. Rozenblatt-Rosen, Kerstin Lindblad-Toh, Katharine Nicholson, Peter Gregersen, J. Lee, O. Butovsky, Matt Brauer, Tara Nickerson, Shameek Biswas, Kimberly A. Wilson, Sulev Kõks, Stephen Muljo, Bryan J. Traynor, Robert Moccia, Seng Cheng, Andrew Deubler, Giovanni Coppola, Mickey Atwal, M. Cantor, W. Salerno, Eli Stahl, Matt Anderson, David Frendewey, Daphne Koller, Mary Rozenman, Jose Norberto S. Vargas, N. Birsa, T. Raj, Jack Humphrey, M. Keuss, O. Wilkins, Michael E. Ward, M. Secrier, P. Fratta
Nature Neuroscience, 2025

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Bryce-Smith, S., Brown, A.-L., Chien, M. Z. Y. J., Dattilo, D., Mehta, P. R., Mattedi, F., … Fratta, P. (2025). TDP-43 loss induces cryptic polyadenylation in ALS/FTD. Nature Neuroscience.

Chicago/Turabian Click to copy
Bryce-Smith, Sam, Anna-Leigh Brown, Max Z. Y. J. Chien, Dario Dattilo, Puja R. Mehta, F. Mattedi, Simone Barattucci, et al. “TDP-43 Loss Induces Cryptic Polyadenylation in ALS/FTD.” Nature Neuroscience (2025).

MLA Click to copy
Bryce-Smith, Sam, et al. “TDP-43 Loss Induces Cryptic Polyadenylation in ALS/FTD.” Nature Neuroscience, 2025.

BibTeX Click to copy

@article{sam2025a,
  title = {TDP-43 loss induces cryptic polyadenylation in ALS/FTD},
  year = {2025},
  journal = {Nature Neuroscience},
  author = {Bryce-Smith, Sam and Brown, Anna-Leigh and Chien, Max Z. Y. J. and Dattilo, Dario and Mehta, Puja R. and Mattedi, F. and Barattucci, Simone and Mikheenko, A. and Zanovello, M. and Pellegrini, F. and El-Agamy, Sara Emad and Yome, Matthew and Hill, Sarah E and Qi, Y. A. and Sun, Kai and Ryadnov, Eugeni and Wan, Yixuan and Arcila-Londono, Hemali Justin Dhruv James R. Zachary Ximena Edward B. Viv Phatnani Kwan Sareen Broach Simmons and Phatnani, Hemali and Kwan, Justin and Sareen, D. and Broach, James R and Simmons, Zachary and Arcila-Londono, Ximena and Lee, Edward B and Deerlin, V. V. Van and Shneider, Neil A. and Fraenkel, Ernest and Ostrow, L. and Baas, Frank and Zaitlen, Noah and Berry, James D. and Malaspina, Andrea and Cox, Gregory A. and Thompson, Leslie M. and Finkbeiner, Steve and Dardiotis, Efthimios and Miller, Timothy M. and Chandran, Siddharthan and Pal, S. and Hornstein, E. and MacGowan, D. and Heiman-Patterson, Terry and Hammell, M. and Patsopoulos, N. and Dubnau, Joshua and Nath, Avindra and Bowser, R. and Harms, Matthew M and Aronica, Eleonora and Poss, Mary and Phillips-Cremins, Jennifer and Crary, John and Atassi, N. and Lange, Dale J. and Adams, Darius J. and Stefanis, Leonidas and Gotkine, M. and Baloh, Robert H. and Babu, Suma and Paganoni, S. and Shalem, Ophir and Smith, Colin and Zhang, Bin and Kwan, Justin and Blanchard, Thomas and Harris, Brent and Broce, Iris J. and Drory, V. and Ravits, J. and McMillan, Corey and Menon, Vilas and Wu, Lani and Altschuler, Steve and Lerner, Y. and Sattler, Rita and Keuren-Jensen, K. Van and Rozenblatt-Rosen, O. and Lindblad-Toh, Kerstin and Nicholson, Katharine and Gregersen, Peter and Lee, J. and Butovsky, O. and Brauer, Matt and Nickerson, Tara and Biswas, Shameek and Wilson, Kimberly A. and Kõks, Sulev and Muljo, Stephen and Traynor, Bryan J. and Moccia, Robert and Cheng, Seng and Deubler, Andrew and Coppola, Giovanni and Atwal, Mickey and Cantor, M. and Salerno, W. and Stahl, Eli and Anderson, Matt and Frendewey, David and Koller, Daphne and Rozenman, Mary and Vargas, Jose Norberto S. and Birsa, N. and Raj, T. and Humphrey, Jack and Keuss, M. and Wilkins, O. and Ward, Michael E. and Secrier, M. and Fratta, P.}
}

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. The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.