Cited by 740Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesAlzheimer's disease research and treatments

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C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

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Mizielinska, Sarah, Grönke, Sebastian, Niccoli, Teresa, Ridler, Charlotte E., Clayton, Emma L., Devoy, Anny, Moens, Thomas, Norona, Frances E., Woollacott, Ione O. C., Pietrzyk, Julian, Cleverley, Karen, Nicoll, Andrew J., Pickering-Brown, Stuart, Dols, Jacqueline, Cabecinha, Melissa, Hendrich, Oliver, Fratta, Pietro, Fisher, Elizabeth M. C., Partridge, Linda, Isaacs, Adrian M.·2014·Science

DOI 10.1126/science.1256800PMC PMC4944841

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Abstract

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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Additional file 4 of Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization
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Additional file 21 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis
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Additional file 1 of Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity
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Additional file 3 of Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization
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Additional file 20 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis
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Additional file 2 of Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization
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Additional file 23 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis
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Additional file 15 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis
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Additional file 24 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis
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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: Mizielinska, Sarah
Grönke, Sebastian
Niccoli, Teresa
Clayton, Emma L.
Devoy, Anny
Moens, Thomas
Norona, Frances E.
Woollacott, Ione O. C.
Cleverley, Karen
Nicoll, Andrew J.
Pickering-Brown, Stuart
Cabecinha, Melissa
Hendrich, Oliver
Fratta, Pietro
Fisher, Elizabeth M. C.
Partridge, Linda
Isaacs, Adrian M.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2014-09-05
Volume: 345
Issue: 6201
Pages: 1192-1194
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1256800
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 › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

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