Structural insight into C9orf72 hexanucleotide repeat expansions: Towards new therapeutic targets in FTD-ALS

•C9orf72 HRE forms DNA and RNA G-quadruplexes with distinct structures.•This review provides an extensive overview of C9orf72 HRE structural polymorphism.•We highlighted the tools and techniques required to study G-quadruplexes.•Therapeutic approaches for the repeat expansion in C9orf72 gene are discussed.

Hexanucleotide repeat expansions, (G4C2) in the C9orf72 gene are considered as the single most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). (G4C2), either as DNA or the transcribed RNA, can folds into unusual secondary structures, including G-quadruplex, R-loop, I-motif and hairpin. These structural polymorphism at both DNA and RNA levels were proposed to initiate molecular cascade leading to ALS/FTD. G-quadruplexes are composed of stacked G4 tetrads, held by hydrophobic bonds, and is highly stable secondary structure. Here, we covers the structural and functional features of G-quadruplexes with an emphasis on C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS). We also highlighted tools and techniques used to study the G-quadruplexes. Current perspectives for molecules that target G-quadruplexes as potential therapeutic are discussed. Our extensive analysis of structural features of G-quadruplexes will be used for a better understanding of molecular mechanism of C9-FTD/ALS.