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Science. 2014 Sep 5;345(6201):1192-1194. doi: 10.1126/science.1256800. Epub 2014 Aug 7.

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

Author information

Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK.
MRC Prion Unit, UCL Institute of Neurology, London WC1N 3BG, UK.
Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Contributed equally


An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted "RNA-only" repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.

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