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Cited by 978Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesDNA and Nucleic Acid Chemistry

C9orf72 nucleotide repeat structures initiate molecular cascades of disease

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Haeusler, Aaron R., Donnelly, Christopher J., Periz, Goran, Simko, Eric A. J., Shaw, Patrick G., Kim, Min-Sik, Maragakis, Nicholas J., Troncoso, Juan C. +4 more·2014·Nature
DOI 10.1038/nature13124PMC PMC4046618
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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.

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  • The GGGGCC repeat expansion suppresses the production of C9ORF72 protein by inhibiting transcription.

    “The GGGGCC repeat expansion suppresses the production of C9ORF72 protein by inhibiting transcription (140, 153, 225, 369, 497, 520).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [225]

    In Results, “Impeded transcription and abortive RNAs” (page unavailable), the paper reports that the expansion impairs RNA polymerase processivity, reducing full-length transcripts; patient-cell and tissue measurements also show evidence of abortive transcription. These passages support the transcriptional part of the claim, but do not establish that C9ORF72 protein production is suppressed. (LLM, conf=0.85)

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Cited by

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Authors
Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., Maragakis, N. J., Troncoso, J. C., Pandey, A., Sattler, R., Rothstein, J. D., & Wang, J.
Affiliations
Johns Hopkins University (US)
Corresponding author
Wang, Jiou
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2014-03
Volume
507
Issue
7491
Pages
195-200
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature13124
PMC
PMC4046618
OpenAlex
W2065219073
Cited by
978
References
6
Citations by year
2026: 34 · 2025: 55 · 2024: 53 · 2023: 71 · 2022: 62 · 2021: 97 · 2020: 91 · 2019: 79 · 2018: 98 · 2017: 69 · 2016: 106 · 2015: 110 · 2014: 53
FWCI
73.49
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (5f32ns007432-02, UL1TR001079)
  • National Institute on Aging (P50AG005146, P50AG05146)
  • National Cancer Institute (T32CA009110)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK089502)
  • National Institute of Neurological Disorders and Stroke (NS085207, R01NS085207, NS07432, R01NS074324)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
C9orf72, hexanucleotide repeat expansion, G-quadruplex, RNA-DNA hybrids, R-loops, nucleolin, nucleolar stress, amyotrophic lateral sclerosis, frontotemporal dementia, truncated transcripts
MeSH terms
Nucleolin, Amyotrophic Lateral Sclerosis, B-Lymphocytes, Base Sequence, Cell Nucleolus, DNA, Humans, Models, Molecular, Neurons, Phosphoproteins, Ribonucleoproteins, RNA, Stress, Physiological, Transcription, Genetic, Open Reading Frames, RNA-Binding Proteins, DNA Repeat Expansion, G-Quadruplexes, Frontotemporal Dementia, HEK293 Cells

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