Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72...

Area of Science:

• Neuroscience
• Molecular Biology
• Structural Biology

Background:

• C9orf72 gene repeat expansions are a primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• These expansions form G-quadruplex (G4) structures, implicated in disease pathogenesis.

Purpose of the Study:

• To elucidate the structural conformations of GGGGCC (G4C2) repeats.
• To provide mechanistic insights into C9orf72-associated neurodegeneration.
• To identify potential structure-based therapeutic targets for ALS and FTD.

Main Methods:

• High-resolution crystal structure determination of parallel G4 conformations.
• Analysis of antiparallel G4 monomeric structure.

Main Results:

• Four DNA G4C2 repeats fold into two distinct G4 conformations: parallel and antiparallel.
• The parallel G4 forms an eight-layered dimer with stacked G-tetrads and unique cytosine quadruple base pairs.
• The antiparallel G4 forms a four-layered monomer with edgewise loops and K+ ion interactions.

Conclusions:

• Distinct G4 structures arise from C9orf72 repeat expansions.
• These structures offer mechanistic understanding of neurodegeneration.
• The identified G4 conformations represent potential targets for novel ALS and FTD therapies.