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Comment
. 2018 Jan;10(1):4-6.
doi: 10.15252/emmm.201708572.

Targeting RNA G-quadruplexes as new treatment strategy for C9orf72 ALS/FTD

Martin H Schludi  1   2 , Dieter Edbauer  1   2
Affiliations
Comment

Targeting RNA G-quadruplexes as new treatment strategy for C9orf72 ALS/FTD

Martin H Schludi et al. EMBO Mol Med. 2018 Jan.

Abstract

The recent discovery of a pathogenic expansion of a (GGGGCC)n repeat in the C9orf72 gene in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) led to a burst of mechanistic discoveries. In this issue, Simone et al (2018) describe novel compounds targeting the G‐quadruplex (G‐Q) structure of the (GGGGCC)n repeat RNA that alleviate the hallmarks of C9orf72 disease in patient‐derived neurons and increase survival in a Drosophila model. Lack of overt off‐target effects and toxicity suggest that these small molecules are promising lead compounds to the development of a therapy.

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Figures

Figure 1
Figure 1. Small molecules stabilize the GGGGCC RNA G‐quadruplex structure
Small aromatic compounds with two amidine residues preferentially interact with the parallel G‐Q of the (GGGGCC)n repeat RNA and stabilize this structure. Stabilization of the G‐quadruplex structure reduces RNA foci formation and inhibits repeat translation. Note that other G‐Q confirmations are possible.
See this image and copyright information in PMC

Comment on

  • G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo.
    Simone R, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, Woodling NS, Niccoli T, Gilbert-Jaramillo J, Abdelkarim S, Clayton EL, Clarke M, Konrad MT, Nicoll AJ, Mitchell JS, Calvo A, Chio A, Houlden H, Polke JM, Ismail MA, Stephens CE, Vo T, Farahat AA, Wilson WD, Boykin DW, Zetterberg H, Partridge L, Wray S, Parkinson G, Neidle S, Patani R, Fratta P, Isaacs AM. Simone R, et al. EMBO Mol Med. 2018 Jan;10(1):22-31. doi: 10.15252/emmm.201707850. EMBO Mol Med. 2018. PMID: 29113975 Free PMC article.

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Publication types

Supplementary concepts