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The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Author

Listed:
  • Ke Zhang

    (School of Medicine, Johns Hopkins University)

  • Christopher J. Donnelly

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

  • Aaron R. Haeusler

    (Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University)

  • Jonathan C. Grima

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

  • James B. Machamer

    (School of Medicine, Johns Hopkins University)

  • Peter Steinwald

    (Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University)

  • Elizabeth L. Daley

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

  • Sean J. Miller

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

  • Kathleen M. Cunningham

    (School of Medicine, Johns Hopkins University)

  • Svetlana Vidensky

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

  • Saksham Gupta

    (School of Medicine, Johns Hopkins University)

  • Michael A. Thomas

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

  • Ingie Hong

    (School of Medicine, Johns Hopkins University)

  • Shu-Ling Chiu

    (School of Medicine, Johns Hopkins University)

  • Richard L. Huganir

    (School of Medicine, Johns Hopkins University)

  • Lyle W. Ostrow

    (School of Medicine, Johns Hopkins University)

  • Michael J. Matunis

    (Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University)

  • Jiou Wang

    (Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University)

  • Rita Sattler

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

  • Thomas E. Lloyd

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

  • Jeffrey D. Rothstein

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

Abstract

The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.

Suggested Citation

  • Ke Zhang & Christopher J. Donnelly & Aaron R. Haeusler & Jonathan C. Grima & James B. Machamer & Peter Steinwald & Elizabeth L. Daley & Sean J. Miller & Kathleen M. Cunningham & Svetlana Vidensky & Sa, 2015. "The C9orf72 repeat expansion disrupts nucleocytoplasmic transport," Nature, Nature, vol. 525(7567), pages 56-61, September.
    • Handle: RePEc:nat:nature:v:525:y:2015:i:7567:d:10.1038_nature14973
    DOI: 10.1038/nature14973
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    Citations

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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. Mirjana Malnar Črnigoj & Urša Čerček & Xiaoke Yin & Manh Tin Ho & Barbka Repic Lampret & Manuela Neumann & Andreas Hermann & Guy Rouleau & Beat Suter & Manuel Mayr & Boris Rogelj, 2023. "Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Yuhao Min & Xue Wang & Özkan İş & Tulsi A. Patel & Junli Gao & Joseph S. Reddy & Zachary S. Quicksall & Thuy Nguyen & Shu Lin & Frederick Q. Tutor-New & Jessica L. Chalk & Adriana O. Mitchell & Julia , 2023. "Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Junhao Li & Manoj K. Jaiswal & Jo-Fan Chien & Alexey Kozlenkov & Jinyoung Jung & Ping Zhou & Mahammad Gardashli & Luc J. Pregent & Erica Engelberg-Cook & Dennis W. Dickson & Veronique V. Belzil & Eran, 2023. "Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    5. Amanda M. Gleixner & Brandie Morris Verdone & Charlton G. Otte & Eric N. Anderson & Nandini Ramesh & Olivia R. Shapiro & Jenna R. Gale & Jocelyn C. Mauna & Jacob R. Mann & Katie E. Copley & Elizabeth , 2022. "NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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