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

Science  05 Sep 2014:
Vol. 345, Issue 6201, pp. 1192-1194
DOI: 10.1126/science.1256800

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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

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, 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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