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Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD

View ORCID ProfileSahba Seddighi, Yue A. Qi, View ORCID ProfileAnna-Leigh Brown, Oscar G. Wilkins, Colleen Bereda, Cedric Belair, Yongjie Zhang, Mercedes Prudencio, Matthew J Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E. Hill, James Hawrot, Daniel M. Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I. Shah, Mike A. Nalls, Jenn Colon-Mercado, Joel F. Reyes, Veronica H. Ryan, Matthew P. Nelson, Casey Cook, Ziyi Li, Laurel Screven, Justin Y Kwan, Anantharaman Shantaraman, Lingyan Ping, Yuka Koike, Björn Oskarsson, Nathan Staff, Duc M. Duong, Aisha Ahmed, View ORCID ProfileMaria Secrier, Jerneg Ule, Steven Jacobson, Jonathan Rohrer, Andrea Malaspina, Jonathan D. Glass, Alessandro Ori, View ORCID ProfileNicholas T. Seyfried, View ORCID ProfileManolis Maragkakis, Leonard Petrucelli, Pietro Fratta, View ORCID ProfileMichael E. Ward
doi: https://doi.org/10.1101/2023.01.23.525149
Sahba Seddighi
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
2Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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  • ORCID record for Sahba Seddighi
Yue A. Qi
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
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Anna-Leigh Brown
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
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  • ORCID record for Anna-Leigh Brown
Oscar G. Wilkins
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
5The Francis Crick Institute, London, UK
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Colleen Bereda
2Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
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Cedric Belair
6Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
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Yongjie Zhang
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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Mercedes Prudencio
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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Matthew J Keuss
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
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Aditya Khandeshi
6Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
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Sarah Pickles
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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Sarah E. Hill
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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James Hawrot
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Daniel M. Ramos
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
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Hebao Yuan
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Jessica Roberts
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
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Erika Kelmer Sacramento
9Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, Germany
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Syed I. Shah
10Data Tecnica International, Washington, DC, USA
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Mike A. Nalls
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
10Data Tecnica International, Washington, DC, USA
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Jenn Colon-Mercado
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Joel F. Reyes
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Veronica H. Ryan
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Matthew P. Nelson
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
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Casey Cook
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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Ziyi Li
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
10Data Tecnica International, Washington, DC, USA
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Laurel Screven
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
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Justin Y Kwan
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Anantharaman Shantaraman
11Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
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Lingyan Ping
11Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
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Yuka Koike
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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Björn Oskarsson
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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Nathan Staff
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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Duc M. Duong
11Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
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Aisha Ahmed
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
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Maria Secrier
14Department of Genetics, Evolution and Environment, UCL Genetics Institute, UCL, London, UK
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Jerneg Ule
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
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Steven Jacobson
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Jonathan Rohrer
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
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Andrea Malaspina
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
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Jonathan D. Glass
13Department of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA
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Alessandro Ori
9Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, Germany
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Nicholas T. Seyfried
11Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
12Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
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Manolis Maragkakis
6Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
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Leonard Petrucelli
7Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
8Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
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  • For correspondence: michael.ward4@nih.gov
Pietro Fratta
4UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
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  • For correspondence: michael.ward4@nih.gov
Michael E. Ward
1National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
3Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
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  • ORCID record for Michael E. Ward
  • For correspondence: michael.ward4@nih.gov
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Abstract

Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to ALS and FTD, leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. However, the possibility of de novo protein synthesis from cryptic exon transcripts has not been explored. Here, we show that mRNA transcripts harboring cryptic exons generate de novo proteins both in TDP-43 deficient cellular models and in disease. Using coordinated transcriptomic and proteomic studies of TDP-43 depleted iPSC-derived neurons, we identified numerous peptides that mapped to cryptic exons. Cryptic exons identified in iPSC models were highly predictive of cryptic exons expressed in brains of patients with TDP-43 proteinopathy, including cryptic transcripts that generated de novo proteins. We discovered that inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Finally, we showed that these de novo peptides were present in CSF from patients with ALS. The demonstration of cryptic exon translation suggests new mechanisms for ALS pathophysiology downstream of TDP-43 dysfunction and may provide a strategy for novel biomarker development.

One Sentence Summary Loss of TDP-43 function results in the expression of de novo proteins from mis-spliced mRNA transcripts.

Competing Interest Statement

MAN, ZL, and SIS's participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. MAN also currently serves as an advisor for Character Biosciences and Neuron23 Inc.

Footnotes

  • https://shorturl.at/HJORU

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD
Sahba Seddighi, Yue A. Qi, Anna-Leigh Brown, Oscar G. Wilkins, Colleen Bereda, Cedric Belair, Yongjie Zhang, Mercedes Prudencio, Matthew J Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E. Hill, James Hawrot, Daniel M. Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I. Shah, Mike A. Nalls, Jenn Colon-Mercado, Joel F. Reyes, Veronica H. Ryan, Matthew P. Nelson, Casey Cook, Ziyi Li, Laurel Screven, Justin Y Kwan, Anantharaman Shantaraman, Lingyan Ping, Yuka Koike, Björn Oskarsson, Nathan Staff, Duc M. Duong, Aisha Ahmed, Maria Secrier, Jerneg Ule, Steven Jacobson, Jonathan Rohrer, Andrea Malaspina, Jonathan D. Glass, Alessandro Ori, Nicholas T. Seyfried, Manolis Maragkakis, Leonard Petrucelli, Pietro Fratta, Michael E. Ward
bioRxiv 2023.01.23.525149; doi: https://doi.org/10.1101/2023.01.23.525149
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Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD
Sahba Seddighi, Yue A. Qi, Anna-Leigh Brown, Oscar G. Wilkins, Colleen Bereda, Cedric Belair, Yongjie Zhang, Mercedes Prudencio, Matthew J Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E. Hill, James Hawrot, Daniel M. Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I. Shah, Mike A. Nalls, Jenn Colon-Mercado, Joel F. Reyes, Veronica H. Ryan, Matthew P. Nelson, Casey Cook, Ziyi Li, Laurel Screven, Justin Y Kwan, Anantharaman Shantaraman, Lingyan Ping, Yuka Koike, Björn Oskarsson, Nathan Staff, Duc M. Duong, Aisha Ahmed, Maria Secrier, Jerneg Ule, Steven Jacobson, Jonathan Rohrer, Andrea Malaspina, Jonathan D. Glass, Alessandro Ori, Nicholas T. Seyfried, Manolis Maragkakis, Leonard Petrucelli, Pietro Fratta, Michael E. Ward
bioRxiv 2023.01.23.525149; doi: https://doi.org/10.1101/2023.01.23.525149

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