RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention
Open accessAbstract
A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.
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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 [153]
The Results section (page not provided) reports approximately 50% lower C9ORF72 V1 and V2 RNA levels in patient CNS tissue and iPSC-derived neurons, with reduced pre-mRNA also observed in CNS tissue. It does not establish that transcription is inhibited, and it explicitly says whether the RNA changes correspond to lower C9ORF72 protein levels is uncertain because the protein could not be specifically quantified. (LLM, conf=0.88)
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Self-citationThams, S., Lowry, E. R., Larraufie, M.-H., Spiller, K. J., Li, H., Williams, D. J., Hoang, P., Jiang, E., Williams, L. A., Sandoe, J., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2018.10.010 · Cited by 51 · see citing works
de Boni, L., Gasparoni, G., Haubenreich, C., Tierling, S., Schmitt, I., Peitz, M., Koch, P., Walter, J., Wüllner, U., & Brüstle, O. (2018) · Clinical Epigenetics · doi:10.1186/s13148-018-0440-0 · Cited by 47 · see citing works
Approaches to gene modulation therapy for ALS
Meijboom, K. E., & Brown, R. H. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01285-w · Cited by 38 · see citing works
Kim, E.-J., Vatsavayai, S., & Seeley, W. W. (2016) · The Behavioral Neurology of Dementia · doi:10.1017/9781139924771.008 · Cited by 7 · see citing works
- Authors
- Donnelly, C. J., Zhang, P.-W., Pham, J. T., Haeusler, A. R., Mistry, N. A., Vidensky, S., Daley, E. L., Poth, E. M., Hoover, B., Fines, D. M., Maragakis, N., Tienari, P. J., Petrucelli, L., Traynor, B. J., Wang, J., Rigo, F., Bennett, C. F., Blackshaw, S., Sattler, R., & Rothstein, J. D.
- Affiliations
- Johns Hopkins University (US)
- University of Helsinki (FI)
- Mayo Clinic in Florida (US)
- National Institutes of Health (US)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Sattler, Rita
- Rothstein, Jeffrey D.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 80
- Issue
- 2
- Pages
- 415-428
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4098943
- OpenAlex
- W2114872355
- Cited by
- 877
- References
- 5
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 34 · 2023: 60 · 2022: 57 · 2021: 73 · 2020: 87 · 2019: 62 · 2018: 91 · 2017: 83 · 2016: 97 · 2015: 100 · 2014: 70 · 2013: 10
- FWCI
- 58.64
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-11-20)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS085207, R01NS074324)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72, GGGGCC repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, antisense oligonucleotides, RNA gain-of-function toxicity, repeat-associated non-ATG translation, excitotoxicity, iPSC-derived neurons, pharmacodynamic biomarkers, RNA foci
- MeSH terms
- C9orf72 Protein, Adenosine Deaminase, Amyotrophic Lateral Sclerosis, Cell Count, Dose-Response Relationship, Drug, Humans, Neurons, Proteins, Repetitive Sequences, Nucleic Acid, RNA, Oligonucleotides, Antisense, RNA-Binding Proteins, Glutamic Acid, Induced Pluripotent Stem Cells, Frontotemporal Dementia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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