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TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Author

Listed:
  • Anna-Leigh Brown

    (UCL Queen Square Institute of Neurology, UCL)

  • Oscar G. Wilkins

    (UCL Queen Square Institute of Neurology, UCL
    The Francis Crick Institute)

  • Matthew J. Keuss

    (UCL Queen Square Institute of Neurology, UCL)

  • Sarah E. Hill

    (National Institute of Neurological Disorders and Stroke, NIH)

  • Matteo Zanovello

    (UCL Queen Square Institute of Neurology, UCL)

  • Weaverly Colleen Lee

    (UCL Queen Square Institute of Neurology, UCL)

  • Alexander Bampton

    (University College London
    University College London)

  • Flora C. Y. Lee

    (UCL Queen Square Institute of Neurology, UCL
    The Francis Crick Institute)

  • Laura Masino

    (The Francis Crick Institute)

  • Yue A. Qi

    (National Institutes of Health)

  • Sam Bryce-Smith

    (UCL Queen Square Institute of Neurology, UCL)

  • Ariana Gatt

    (University College London
    University College London)

  • Martina Hallegger

    (UCL Queen Square Institute of Neurology, UCL
    The Francis Crick Institute)

  • Delphine Fagegaltier

    (New York Genome Center (NYGC))

  • Hemali Phatnani

    (New York Genome Center (NYGC))

  • Jia Newcombe

    (UCL Queen Square Institute of Neurology)

  • Emil K. Gustavsson

    (University College London
    University College London)

  • Sahba Seddighi

    (National Institute of Neurological Disorders and Stroke, NIH
    Johns Hopkins University School of Medicine)

  • Joel F. Reyes

    (National Institute of Neurological Disorders and Stroke, NIH)

  • Steven L. Coon

    (Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH)

  • Daniel Ramos

    (National Institute of Neurological Disorders and Stroke, NIH
    National Institutes of Health)

  • Giampietro Schiavo

    (UCL Queen Square Institute of Neurology, UCL
    University College London)

  • Elizabeth M. C. Fisher

    (UCL Queen Square Institute of Neurology, UCL)

  • Towfique Raj

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Maria Secrier

    (University College London)

  • Tammaryn Lashley

    (University College London
    University College London)

  • Jernej Ule

    (UCL Queen Square Institute of Neurology, UCL
    The Francis Crick Institute
    National Institute of Chemistry)

  • Emanuele Buratti

    (Molecular Pathology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB))

  • Jack Humphrey

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Michael E. Ward

    (National Institute of Neurological Disorders and Stroke, NIH)

  • Pietro Fratta

    (UCL Queen Square Institute of Neurology, UCL)

Abstract

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1–3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Suggested Citation

  • Anna-Leigh Brown & Oscar G. Wilkins & Matthew J. Keuss & Sarah E. Hill & Matteo Zanovello & Weaverly Colleen Lee & Alexander Bampton & Flora C. Y. Lee & Laura Masino & Yue A. Qi & Sam Bryce-Smith & Ar, 2022. "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A," Nature, Nature, vol. 603(7899), pages 131-137, March.
    • Handle: RePEc:nat:nature:v:603:y:2022:i:7899:d:10.1038_s41586-022-04436-3
    DOI: 10.1038/s41586-022-04436-3
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    Cited by:

    1. Salim Megat & Natalia Mora & Jason Sanogo & Olga Roman & Alberto Catanese & Najwa Ouali Alami & Axel Freischmidt & Xhuljana Mingaj & Hortense Calbiac & François Muratet & Sylvie Dirrig-Grosch & Stépha, 2023. "Integrative genetic analysis illuminates ALS heritability and identifies risk genes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Hannah E. Salapa & Patricia A. Thibault & Cole D. Libner & Yulian Ding & Joseph-Patrick W. E. Clarke & Connor Denomy & Catherine Hutchinson & Hashim M. Abidullah & S. Austin Hammond & Landon Pastushok, 2024. "hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Santiago Mora & Anna Stuckert & Rasmus Huth Friis & Kimberly Pietersz & Gith Noes-Holt & Roser Montañana-Rosell & Haoyu Wang & Andreas Toft Sørensen & Raghavendra Selvan & Joost Verhaagen & Ilary Allo, 2024. "Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Kurt Farrell & Jack Humphrey & Timothy Chang & Yi Zhao & Yuk Yee Leung & Pavel P. Kuksa & Vishakha Patil & Wan-Ping Lee & Amanda B. Kuzma & Otto Valladares & Laura B. Cantwell & Hui Wang & Ashvin Ravi, 2024. "Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Yufeng Liang & Sydney Willey & Yu-Chieh Chung & Yi-Meng Lo & Shiqin Miao & Sarah Rundell & Li-Chun Tu & Dennis Bong, 2023. "Intracellular RNA and DNA tracking by uridine-rich internal loop tagging with fluorogenic bPNA," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Oliver J. Ziff & Jacob Neeves & Jamie Mitchell & Giulia Tyzack & Carlos Martinez-Ruiz & Raphaelle Luisier & Anob M. Chakrabarti & Nicholas McGranahan & Kevin Litchfield & Simon J. Boulton & Ammar Al-C, 2023. "Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Jarrett Eshima & Samantha A. O’Connor & Ethan Marschall & Robert Bowser & Christopher L. Plaisier & Barbara S. Smith, 2023. "Molecular subtypes of ALS are associated with differences in patient prognosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Rebecca San Gil & Dana Pascovici & Juliana Venturato & Heledd Brown-Wright & Prachi Mehta & Lidia Madrid San Martin & Jemma Wu & Wei Luan & Yi Kit Chui & Adekunle T. Bademosi & Shilpa Swaminathan & Se, 2024. "A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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