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Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD

Author

Listed:
  • Shaopeng Wang

    (Johns Hopkins University School of Medicine
    Brain Science Institute, Johns Hopkins University School of Medicine)

  • Malgorzata J. Latallo

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Zhe Zhang

    (Johns Hopkins University School of Medicine
    Brain Science Institute, Johns Hopkins University School of Medicine)

  • Bo Huang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Dmitriy G. Bobrovnikov

    (Johns Hopkins University School of Medicine)

  • Daoyuan Dong

    (Johns Hopkins University School of Medicine
    Brain Science Institute, Johns Hopkins University School of Medicine)

  • Nathan M. Livingston

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Wilson Tjoeng

    (Johns Hopkins University School of Medicine
    Brain Science Institute, Johns Hopkins University School of Medicine)

  • Lindsey R. Hayes

    (Brain Science Institute, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Jeffrey D. Rothstein

    (Brain Science Institute, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Lyle W. Ostrow

    (Johns Hopkins University School of Medicine)

  • Bin Wu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Shuying Sun

    (Johns Hopkins University School of Medicine
    Brain Science Institute, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

C9ORF72 hexanucleotide GGGGCC repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-containing RNA mediates toxicity through nuclear granules and dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG translation. However, it remains unclear how the intron-localized repeats are exported and translated in the cytoplasm. We use single molecule imaging approach to examine the molecular identity and spatiotemporal dynamics of the repeat RNA. We demonstrate that the spliced intron with G-rich repeats is stabilized in a circular form due to defective lariat debranching. The spliced circular intron, instead of pre-mRNA, serves as the translation template. The NXF1-NXT1 pathway plays an important role in the nuclear export of the circular intron and modulates toxic DPR production. This study reveals an uncharacterized disease-causing RNA species mediated by repeat expansion and demonstrates the importance of RNA spatial localization to understand disease etiology.

Suggested Citation

  • Shaopeng Wang & Malgorzata J. Latallo & Zhe Zhang & Bo Huang & Dmitriy G. Bobrovnikov & Daoyuan Dong & Nathan M. Livingston & Wilson Tjoeng & Lindsey R. Hayes & Jeffrey D. Rothstein & Lyle W. Ostrow &, 2021. "Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25082-9
    DOI: 10.1038/s41467-021-25082-9
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    Cited by:

    1. Lauren A. Blake & Leslie Watkins & Yang Liu & Takanari Inoue & Bin Wu, 2024. "A rapid inducible RNA decay system reveals fast mRNA decay in P-bodies," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Anna B. Loveland & Egor Svidritskiy & Denis Susorov & Soojin Lee & Alexander Park & Sarah Zvornicanin & Gabriel Demo & Fen-Biao Gao & Andrei A. Korostelev, 2022. "Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Malgorzata J. Latallo & Shaopeng Wang & Daoyuan Dong & Blake Nelson & Nathan M. Livingston & Rong Wu & Ning Zhao & Timothy J. Stasevich & Michael C. Bassik & Shuying Sun & Bin Wu, 2023. "Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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