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C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Author

Listed:
  • Aaron R. Haeusler

    (Johns Hopkins University Baltimore
    Johns Hopkins University Baltimore)

  • Christopher J. Donnelly

    (Johns Hopkins University Baltimore
    The Brain Science Institute, Johns Hopkins University Baltimore)

  • Goran Periz

    (Johns Hopkins University Baltimore
    Johns Hopkins University Baltimore)

  • Eric A. J. Simko

    (Johns Hopkins University Baltimore
    Johns Hopkins University Baltimore)

  • Patrick G. Shaw

    (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore)

  • Min-Sik Kim

    (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore)

  • Nicholas J. Maragakis

    (Johns Hopkins University Baltimore)

  • Juan C. Troncoso

    (Johns Hopkins University Baltimore)

  • Akhilesh Pandey

    (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Baltimore)

  • Rita Sattler

    (Johns Hopkins University Baltimore
    The Brain Science Institute, Johns Hopkins University Baltimore)

  • Jeffrey D. Rothstein

    (Johns Hopkins University Baltimore
    Johns Hopkins University Baltimore
    The Brain Science Institute, Johns Hopkins University Baltimore)

  • Jiou Wang

    (Johns Hopkins University Baltimore
    Johns Hopkins University Baltimore)

Abstract

A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.

Suggested Citation

  • Aaron R. Haeusler & Christopher J. Donnelly & Goran Periz & Eric A. J. Simko & Patrick G. Shaw & Min-Sik Kim & Nicholas J. Maragakis & Juan C. Troncoso & Akhilesh Pandey & Rita Sattler & Jeffrey D. Ro, 2014. "C9orf72 nucleotide repeat structures initiate molecular cascades of disease," Nature, Nature, vol. 507(7491), pages 195-200, March.
    • Handle: RePEc:nat:nature:v:507:y:2014:i:7491:d:10.1038_nature13124
    DOI: 10.1038/nature13124
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    Citations

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    Cited by:

    1. Emily L. Spaulding & Alexis M. Feidler & Lio A. Cook & Dustin L. Updike, 2022. "RG/RGG repeats in the C. elegans homologs of Nucleolin and GAR1 contribute to sub-nucleolar phase separation," Nature Communications, Nature, vol. 13(1), pages 1-15, 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. Geng Liu & Wenya Du & Xiongbo Sang & Qiyu Tong & Ye Wang & Guoqing Chen & Yi Yuan & Lili Jiang & Wei Cheng & Dan Liu & Yan Tian & Xianghui Fu, 2022. "RNA G-quadruplex in TMPRSS2 reduces SARS-CoV-2 infection," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. 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.
    5. Zhefan Stephen Chen & Mingxi Ou & Stephanie Taylor & Ruxandra Dafinca & Shaohong Isaac Peng & Kevin Talbot & Ho Yin Edwin Chan, 2023. "Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Kazuki Ichikawa & Riki Kawahara & Takeshi Asano & Shinichi Morishita, 2023. "A landscape of complex tandem repeats within individual human genomes," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Jing Tu & Mengqin Duan & Wenli Liu & Na Lu & Yue Zhou & Xiao Sun & Zuhong Lu, 2021. "Direct genome-wide identification of G-quadruplex structures by whole-genome resequencing," Nature Communications, Nature, vol. 12(1), pages 1-9, December.

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