Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs
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Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.
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Various pathogenic mechanisms have been proposed for C9orf72 repeat expansion toxicity, including toxic inclusions of abnormally expanded RNA, toxic gain of function from dipeptides abnormally transcribed from the expanded RNA, and haploinsufficiency.
“Various pathogenic mechanisms have been proposed for C9orf72 repeat expansion toxicity, including toxic inclusions of abnormally expanded RNA, toxic gain of function from dipeptides abnormally transcribed from the expanded RNA, and haploinsufficiency.84,85”
From Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations (2022) · cites this paper as [85]
The Introduction describes all three proposed mechanisms: C9ORF72 haploinsufficiency, toxicity from repeat-containing RNA foci, and toxicity from dipeptide-repeat proteins. It specifies that the dipeptide-repeat proteins are produced from the RNAs by RAN translation, not transcription, as the claim states. (LLM, conf=0.84)
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ALS Genetics: Gains, Losses, and Implications for Future Therapies
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Antisense Oligonucleotide Therapies for Neurodegenerative Diseases
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Self-citationC9orf72 suppresses systemic and neural inflammation induced by gut bacteria
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Neuroinflammation in frontotemporal dementia
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Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models
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“…of C9orf72 from birth in mice does show abnormalities (Jiang et al., 2016; O’Rourke et al., 2016), raising some concerns for an ASO-mediated lowering strategy, the short-term administration of ASO to the endogenous mouse homolog was well tolerated (Jiang et al., 2016; Lagier-Tourenne et al., 2013).”
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Self-citationTruncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
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Self-citationThe overlapping genetics of amyotrophic lateral sclerosis and frontotemporal dementia
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Self-citationImaging and fluid biomarkers in frontotemporal dementia
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Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling
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<i>C9orf72</i> poly(GR) aggregation induces TDP-43 proteinopathy
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Self-citationAntisense drugs make sense for neurological diseases
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- Authors
- Jiang, J., Zhu, Q., Gendron, T. F., Saberi, S., McAlonis-Downes, M., Seelman, A., Stauffer, J. E., Jafar-nejad, P., Drenner, K., Schulte, D., Chun, S., Sun, S., Ling, S.-C., Myers, B., Engelhardt, J., Katz, M., Baughn, M., Platoshyn, O., Marsala, M., Watt, A., Heyser, C. J., Ard, M. C., De Muynck, L., Daughrity, L. M., Swing, D. A., Tessarollo, L., Jung, C. J., Delpoux, A., Utzschneider, D. T., Hedrick, S. M., de Jong, P. J., Edbauer, D., Van Damme, P., Petrucelli, L., Shaw, C. E., Bennett, C. F., Da Cruz, S., Ravits, J., Rigo, F., Cleveland, D. W., & Lagier-Tourenne, C.
- Affiliations
- University of California San Diego (US)
- Mayo Clinic (US)
- Ionis Pharmaceuticals (United States) (US)
- National University of Singapore (SG)
- National Cancer Institute (US)
- German Center for Neurodegenerative Diseases (DE)
- King's College London (GB)
- Corresponding author
- Cleveland, Don W.
- ORCID
- Jiang, Jie
- Zhu, Qiang
- Gendron, Tania F.
- Stauffer, Jennifer E.
- Sun, Shuying
- Ling, Shuo-Chien
- Baughn, Michael
- Platoshyn, Oleksandr
- Heyser, Charles J.
- Daughrity, Lillian M.
- Tessarollo, Lino
- Delpoux, Arnaud
- Utzschneider, Daniel T.
- Edbauer, Dieter
- Petrucelli, Leonard
- Shaw, Christopher E.
- Bennett, C. Frank
- Ravits, John
- Rigo, Frank
- Cleveland, Don W.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 90
- Issue
- 3
- Pages
- 535-550
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4860075
- OpenAlex
- W2338545563
- Cited by
- 536
- References
- 68
- Citations by year
- 2026: 21 · 2025: 32 · 2024: 49 · 2023: 37 · 2022: 54 · 2021: 70 · 2020: 79 · 2019: 54 · 2018: 57 · 2017: 58 · 2016: 24 · 2015: 1
- FWCI
- 48.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Johns Hopkins University
- Ludwig Institute for Cancer Research
- Target ALS
- Ionis Pharmaceuticals
- European Commission (617198)
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- National Institutes of Health (NS084974, NS063964)
- University of California, San Diego
- Medical Research Council (MR/L021803/1)
- National Institute on Aging (P50AG005131, T32AG000216)
- National Institute of General Medical Sciences (T32GM008666)
- National Institute of Allergy and Infectious Diseases (R01AI103440)
- National Institute of Neurological Disorders and Stroke (R01NS063964, R01NS087227, R01NS077402, K99NS091538, R21NS089979, P01NS084974, R21NS084528, R01NS088689, F32NS087842, R01NS088578)
- Robert Packard Center for ALS Research, Johns Hopkins University
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- C9orf72, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, antisense oligonucleotides, dipeptide repeat proteins, RNA foci, RNA-targeted therapeutics, hippocampal neuronal loss, anxiety, cognitive impairment, splenomegaly
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Mice, Transgenic, Neurons, RNA, Oligonucleotides, Antisense, Guanine Nucleotide Exchange Factors, DNA Repeat Expansion, Frontotemporal Dementia
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