Mizielinska, S; Grönke, S; Niccoli, T; Ridler, CE; Clayton, EL; Devoy, A; Moens, T; ... Isaacs, AM; + view all Mizielinska, S; Grönke, S; Niccoli, T; Ridler, CE; Clayton, EL; Devoy, A; Moens, T; Norona, FE; Woollacott, IOC; Pietrzyk, J; Cleverley, K; Nicoll, AJ; Pickering-Brown, S; Dols, J; Cabecinha, M; Hendrich, O; Fratta, P; Fisher, EMC; Partridge, L; Isaacs, AM; - view fewer (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 10.1126/science.1256800.

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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.

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