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Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization

View ORCID ProfileAnna-Leigh Brown, View ORCID ProfileOscar G. Wilkins, View ORCID ProfileMatthew J. Keuss, View ORCID ProfileSarah E. Hill, View ORCID ProfileMatteo Zanovello, View ORCID ProfileWeaverly Colleen Lee, View ORCID ProfileFlora C.Y. Lee, Laura Masino, Yue A. Qi, View ORCID ProfileSam Bryce-Smith, View ORCID ProfileAlexander Bampton, View ORCID ProfileAriana Gatt, Hemali Phatnani, NYGC ALS Consortium, View ORCID ProfileGiampietro Schiavo, View ORCID ProfileElizabeth M.C. Fisher, View ORCID ProfileTowfique Raj, View ORCID ProfileMaria Secrier, View ORCID ProfileTammaryn Lashley, View ORCID ProfileJernej Ule, View ORCID ProfileEmanuele Buratti, View ORCID ProfileJack Humphrey, View ORCID ProfileMichael E. Ward, View ORCID ProfilePietro Fratta
doi: https://doi.org/10.1101/2021.04.02.438170
Anna-Leigh Brown
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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Oscar G. Wilkins
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
2The Francis Crick Institute, London, UK
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Matthew J. Keuss
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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Sarah E. Hill
3National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Matteo Zanovello
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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Weaverly Colleen Lee
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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  • ORCID record for Weaverly Colleen Lee
Flora C.Y. Lee
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
2The Francis Crick Institute, London, UK
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Laura Masino
2The Francis Crick Institute, London, UK
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Yue A. Qi
3National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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Sam Bryce-Smith
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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Alexander Bampton
4Queen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London, UK
5Queen Square Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, UK
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Ariana Gatt
4Queen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London, UK
5Queen Square Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, UK
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Hemali Phatnani
6Center for Genomics of Neurodegenerative Disease, New York Genome Center (NYGC), New York, NY, USA
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7The NYGC ALS Consortium is detailed in supplemental acknowledgments.
Giampietro Schiavo
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
8Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Elizabeth M.C. Fisher
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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Towfique Raj
8Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
9Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
10Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
11Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Maria Secrier
12Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, UK
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Tammaryn Lashley
4Queen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London, UK
5Queen Square Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, UK
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Jernej Ule
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
2The Francis Crick Institute, London, UK
13Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Ljubljana, Slovenia.
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Emanuele Buratti
14Molecular Pathology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
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Jack Humphrey
8Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
9Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
10Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
11Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Michael E. Ward
3National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
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  • ORCID record for Michael E. Ward
  • For correspondence: p.fratta@ucl.ac.uk michael.ward4@nih.gov
Pietro Fratta
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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  • For correspondence: p.fratta@ucl.ac.uk michael.ward4@nih.gov
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Abstract

Variants within the UNC13A gene have long been known to increase risk of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here, we show that TDP-43 depletion induces robust inclusion of a cryptic exon (CE) within UNC13A, a critical synaptic gene, resulting in nonsense-mediated decay and protein loss. Strikingly, two common polymorphisms strongly associated with ALS/FTD risk directly alter TDP-43 binding within the CE or downstream intron, increasing CE inclusion in cultured cells and in patient brains. Our findings, which are the first to demonstrate a genetic link specifically between loss of TDP-43 nuclear function and disease, reveal both the mechanism by which UNC13A variants exacerbate the effects of decreased nuclear TDP-43 function, and provide a promising therapeutic target for TDP-43 proteinopathies.

One-Sentence Summary Shared ALS/FTD risk variants increase the sensitivity of a cryptic exon in the synaptic gene UNC13A to TDP-43 depletion.

Competing Interest Statement

ALB, OGW, MJK, SEH, MEW and PF declare competing financial interest. A patent application related to this work has been filed.

Footnotes

  • https://github.com/frattalab/unc13a_cryptic_splicing/

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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Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization
Anna-Leigh Brown, Oscar G. Wilkins, Matthew J. Keuss, Sarah E. Hill, Matteo Zanovello, Weaverly Colleen Lee, Flora C.Y. Lee, Laura Masino, Yue A. Qi, Sam Bryce-Smith, Alexander Bampton, Ariana Gatt, Hemali Phatnani, NYGC ALS Consortium, Giampietro Schiavo, Elizabeth M.C. Fisher, Towfique Raj, Maria Secrier, Tammaryn Lashley, Jernej Ule, Emanuele Buratti, Jack Humphrey, Michael E. Ward, Pietro Fratta
bioRxiv 2021.04.02.438170; doi: https://doi.org/10.1101/2021.04.02.438170
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Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization
Anna-Leigh Brown, Oscar G. Wilkins, Matthew J. Keuss, Sarah E. Hill, Matteo Zanovello, Weaverly Colleen Lee, Flora C.Y. Lee, Laura Masino, Yue A. Qi, Sam Bryce-Smith, Alexander Bampton, Ariana Gatt, Hemali Phatnani, NYGC ALS Consortium, Giampietro Schiavo, Elizabeth M.C. Fisher, Towfique Raj, Maria Secrier, Tammaryn Lashley, Jernej Ule, Emanuele Buratti, Jack Humphrey, Michael E. Ward, Pietro Fratta
bioRxiv 2021.04.02.438170; doi: https://doi.org/10.1101/2021.04.02.438170

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