C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins
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Dipeptide repeat peptides on the attack: Certain neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are associated with expanded dipeptides translated from RNA transcripts of disease-associated genes (see the Perspective by West and Gitler). Kwon et al. show that the peptides encoded by the expanded repeats in the C9orf72 gene interfere with the way cells make RNA and kill cells. These effects may account for how this genetic form of ALS causes disease. Working in Drosophila , Mizielinska et al. aimed to distinguish between the effects of repeat-containing RNAs and the dipeptide repeat peptides that they encode. The findings provide evidence that dipeptide repeat proteins can cause toxicity directly. Science , this issue p. 1139 and p. 1192 ; see also p. 1118
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C9orf72 carriers account for the largest amount of familial FTD cases, in which abnormal GGGGCC expansions produce toxic RNA foci and dipeptide repeat proteins.
“These carriers account for the largest amount of familial cases of FTD, in which abnormal GGGGCC expansions in the non‐coding region of the C9orf72 gene produce toxic RNA foci 41 , 42 and dipeptide repeat proteins (DPRs).”
From New developments of biofluid‐based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia (2022) · cites this paper as [43]
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- Authors
- Mizielinska, S., Grönke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., Moens, T., Norona, F. E., Woollacott, I. O. C., Pietrzyk, J., Cleverley, K., Nicoll, A. J., Pickering-Brown, S., Dols, J., Cabecinha, M., Hendrich, O., Fratta, P., Fisher, E. M. C., Partridge, L., & Isaacs, A. M.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- Max Planck Institute for Biology of Ageing (DE)
- MRC Prion Unit (GB)
- University of Manchester (GB)
- University College London (GB)
- Corresponding author
- Mizielinska, Sarah
- Grönke, Sebastian
- Niccoli, Teresa
- Partridge, Linda
- Isaacs, Adrian M.
- ORCID
- Venue
- Science
- Published
- 2014-09-05
- Volume
- 345
- Issue
- 6201
- Pages
- 1192-1194
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4944841
- OpenAlex
- W2137039075
- Cited by
- 740
- References
- 37
- Citations by year
- 2026: 30 · 2025: 44 · 2024: 49 · 2023: 70 · 2022: 57 · 2021: 90 · 2020: 69 · 2019: 62 · 2018: 62 · 2017: 62 · 2016: 68 · 2015: 59 · 2014: 18
- FWCI
- 45.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust (098565, 089701, 081394)
- Brain Research UK (13173)
- National Institute for Health and Care Research (ACF-2012-18-009)
- Motor Neurone Disease Association (ISAACS/APR13/818-791)
- Institute on the Environment, University of Minnesota
- Medical Research Council (MR/K018523/1, MR/J004022/1, MR/L021056/1)
- 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, dipeptide repeat proteins, repeat-associated non-ATG translation, frontotemporal dementia, amyotrophic lateral sclerosis, neurodegeneration, arginine-rich proteins, Drosophila model
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Dipeptides, Disease Models, Animal, Drosophila melanogaster, Escherichia coli, Humans, Neurons, Proteins, DNA Repeat Expansion, Cell Line, Tumor, Frontotemporal Dementia
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