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The large expansion of GGGGCC (G4C2) repeats of the  C9orf72  gene have been found to lead to the pathogenesis of devastating neurological diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The structural polymorphisms of  C9orf72  HRE DNA and RNA may cause aberrant transcription and contribute to the development of ALS and FTD. Here we showed that the two-repeat G4C2 DNA, d(G4C2) 2 , simultaneously formed parallel and antiparallel G-quadruplex conformations in the potassium solution. We separated different folds of d(G4C2) 2  by anion exchange chromatography, followed with characterizations by circular dichroism and nuclear magnetic resonance spectroscopy. The parallel d(G4C2) 2  G-quadruplex folded as a symmetric tetramer, while the antiparallel d(G4C2) 2  adopted the topology of an asymmetric dimer. These folds are distinct from the antiparallel chair-type conformation we previously identified for the d(G4C2) 4  G-quadruplex. Our findings have demonstrated the conformational heterogeneity of the  C9orf72  HRE DNA, and provided new insights into the d(G4C2) n  folding. Meanwhile, the purified d(G4C2) 2  G-quadruplex samples are suitable for further three-dimensional structure characterizations, which are required for the structure-based design of small molecules targeting ALS and FTD related  C9orf72  HRE.

Characterizations of distinct parallel and antiparallel G-quadruplexes formed by two-repeat ALS and FTD related GGGGCC sequence