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

Mizielinska, S; Grönke, S; Niccoli, T; Ridler, CE; Clayton, EL; Devoy, A; Moens, T; ... Isaacs, AM; + view all (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 10.1126/science.1256800. Green open access

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Abstract

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 in Drosophila caused adult-onset neurodegeneration attributable to poly-(glycine-arginine) proteins. Thus, expanded repeats promoted neurodegeneration through neurotoxic proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence showed 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.

Type: Article
Title: C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/science.1256800
Publisher version: http://www.sciencemag.org/cgi/rapidpdf/science.125...
Language: English
Additional information: This is the authors' version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 7 August 2014. DOI: 10.1126/science.1256800. The final, copy-edited version of this work is available at: http://www.sciencemag.org/cgi/rapidpdf/science.1256800?ijkey=UEYruTZZ4BGL6&keytype=ref&siteid=sci
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Clinical and Experimental Epilepsy
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Neurodegenerative Diseases
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment
URI: http://discovery.ucl.ac.uk/id/eprint/1437285
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