Characterization of DNA G-quadruplex species forming from C9ORF72 G4C2-expanded repeats associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Šket, Primož; Pohleven, Jure; Kovanda, Anja; Štalekar, Maja; Župunski, Vera; Zalar, Matja; Plavec, Janez; Rogelj, Boris

doi:10.1016/j.neurobiolaging.2014.09.012

Cited by 65 publications

(68 citation statements)

References 42 publications

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“…DNA and RNA C9orf72 HREs have been shown to form both G‐Qs and hairpin structures (Fratta et al , ; Reddy et al , ; Haeusler et al , ; Su et al , ; Sket et al , ). It is widely accepted that HREs exert a toxic gain of function, either linked to RNA‐mediated sequestration of RBPs in RNA foci, or through translation into toxic DPRs (Mizielinska & Isaacs, ).…”

Section: Discussionmentioning

confidence: 99%

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

Simone¹,

et al. 2017

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Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA‐binding proteins and through toxic dipeptide repeat proteins generated by repeat‐associated non‐ATG translation. GGGGCC repeat RNA folds into a G‐quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G‐quadruplex RNA. We investigated their effect in C9orf72 patient iPSC‐derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat‐expressing Drosophila. Therefore, small molecules that target GGGGCC repeat G‐quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS. These data provide proof of principle that targeting GGGGCC repeat G‐quadruplexes has therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

Simone¹,

et al. 2017

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“…; Sket et al . ). In more expanded repeats, there is a length‐dependent enhancement in the formation of multi‐molecular G‐quadruplex structures, which may influence the ability of the RNA to form foci and bind proteins (Reddy et al .…”

Section: G‐quadruplexes Rna Foci and The Sequestration Of Rbpsmentioning

confidence: 97%

Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions

Todd

Petrucelli

2016

Journal of Neurochemistry

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The identification of a hexanucleotide repeat expansion in a non-coding region of C9orf72 as a major cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) drastically changed the field of research on both of these conditions. Yet, despite the vast amount of work aimed at elucidating the molecular mechanisms underlying the role of this repeat in disease, the exact pathomechanisms are still unclear. A reduction in the expression of the C9orf72 gene is observed in patients, but a gain-of-function model is now preferred. The hexanucleotide repeat expansion forms RNA foci in the central nervous system (CNS) of repeat-positive FTD and ALS patients, and these foci are believed to sequester RNA-binding proteins (RBPs) and impair their function in RNA processing. At the same time, the repeat undergoes repeat-associated non-ATG translation to produce dipeptide repeat proteins that also form inclusions in the patient CNS. Studies from cells and flies suggest that these proteins may also be an important factor in the disease. Finally, the hexanucleotide repeat also induces the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) through an as yet unknown mechanism. This review covers the different potential pathogenic factors that have been put forth for C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS), while highlighting some remaining questions.

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“…In eukaryotes G4s have been reported to be involved in key regulatory roles, including transcriptional regulation of gene promoters and enhancers, translation, chromatin epigenetic regulation, DNA recombination 6-10 . Expansion of G4-forming motifs has been associated with relevant human neurological disorders 8,11 . Formation of G4s in vivo has been consolidated by the discovery of cellular proteins that specifically recognize G4s 12, 13 and the Published: xx xx xxxx OPEN www.nature.com/scientificreports/…”

mentioning

confidence: 99%

Mapping and characterization of G-quadruplexes in Mycobacterium tuberculosis gene promoter regions

Perrone

Lavezzo

Riello

et al. 2017

Sci Rep

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Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), one of the top 10 causes of death worldwide in 2015. The recent emergence of strains resistant to all current drugs urges the development of compounds with new mechanisms of action. G-quadruplexes are nucleic acids secondary structures that may form in G-rich regions to epigenetically regulate cellular functions. Here we implemented a computational tool to scan the presence of putative G-quadruplex forming sequences in the genome of Mycobacterium tuberculosis and analyse their association to transcription start sites. We found that the most stable G-quadruplexes were in the promoter region of genes belonging to definite functional categories. Actual G-quadruplex folding of four selected sequences was assessed by biophysical and biomolecular techniques: all molecules formed stable G-quadruplexes, which were further stabilized by two G-quadruplex ligands. These compounds inhibited Mycobacterium tuberculosis growth with minimal inhibitory concentrations in the low micromolar range. These data support formation of Mycobacterium tuberculosis G-quadruplexes in vivo and their potential regulation of gene transcription, and prompt the use of G4 ligands to develop original antitubercular agents.

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Characterization of DNA G-quadruplex species forming from C9ORF72 G4C2-expanded repeats associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Cited by 65 publications

References 42 publications

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD / ALS pathology in vitro and in vivo

Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions

Mapping and characterization of G-quadruplexes in Mycobacterium tuberculosis gene promoter regions

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