Fratta, P; Mizielinska, S; Nicoll, AJ; Zloh, M; Fisher, EM; Parkinson, G; Isaacs, AM; (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Scientific Reports , 2 , Article 1016. 10.1038/srep01016.

Preview	PDF srep01016.pdf Download (597kB)
Preview	Other (JPG Figure 1: Schematic representation of the parallel stranded GGGGCC RNA G-quadruplex.) srep01016-f1.jpg Download (192kB)
Preview	Other (JPG Figure 2: The C9orf72 hexanucleotide repeat is predicted to form a G-quadruplex structure.) srep01016-f2.jpg Download (74kB)
Preview	Other (JPG Figure 3: NMR analysis of the C9orf72 GGGGCC RNA hexanucleotide repeat shows formation of G-quadruplexes.) srep01016-f3.jpg Download (59kB)
Preview	Other (JPG Figure 4: CD analysis shows the GGGGCC RNA G-quadruplex structures are very stable, cation dependent and parallel oriented.) srep01016-f4.jpg Download (129kB)
Preview	PDF (Supplementary Information) srep01016-s1.pdf Download (529kB)

Abstract

Large expansions of a non-coding GGGGCC-repeat in the first intron of the C9orf72 gene are a common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). G-rich sequences have a propensity for forming highly stable quadruplex structures in both RNA and DNA termed G-quadruplexes. G-quadruplexes have been shown to be involved in a range of processes including telomere stability and RNA transcription, splicing, translation and transport. Here we show using NMR and CD spectroscopy that the C9orf72 hexanucleotide expansion can form a stable G-quadruplex, which has profound implications for disease mechanism in ALS and FTD.

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