Related Experiment Video
Updated: Jul 29, 2025
08:17
Practical Aspects of Sample Preparation and Setup of 1H R1ρ Relaxation Dispersion Experiments of RNA
Published on: July 9, 2021
4.8K
Conformational dynamics of RNA G4C2 and G2C4 repeat expansions causing ALS/FTD using NMR and molecular dynamics
Amirhossein Taghavi1, Jared T Baisden1, Jessica L Childs-Disney1
1Department of Chemistry, Scripps Research and The Herbert Wertheim UF-Scripps Institute for Biomedical Research & Innovation, 130 Scripps Way, 3A1 Jupiter, FL 33458, USA.
Nucleic Acids Research
|May 22, 2023
Summary
Repeat expansions in C9orf72 cause ALS and FTD. Studies reveal r(G4C2)exp hairpin structures are sensitive to stacking interactions, unlike r(G2C4)exp, informing drug design for neurodegenerative diseases.
Area of Science:
- Molecular Biology
- Neurogenetics
- Structural Biology
Background:
- C9orf72 (chromosome 9 open reading frame 72) repeat expansions are the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- These expansions produce bidirectionally transcribed RNA repeats: r(G4C2)exp and r(G2C4)exp.
- Previous studies indicated r(G4C2)exp forms hairpin structures with G-quadruplexes or internal loops, while r(G2C4)exp forms different loop structures.
Purpose of the Study:
- To investigate the conformational dynamics of the 2x2 GG/GG internal loops within r(G4C2)exp.
- To characterize the structure and dynamics of these loops using advanced biophysical techniques.
- To compare the structural dynamics of r(G4C2)exp loops with those of r(G2C4)exp.
Main Methods:
- Temperature replica exchange molecular dynamics (T-REMD) simulations to study conformational dynamics.
- Traditional 2D Nuclear Magnetic Resonance (NMR) spectroscopy for structural and dynamic characterization.
- Analysis of loop closing base pair influence on structure and dynamics.
Main Results:
- r(G4C2)exp adopts hairpin structures with 2x2 GG/GG internal loops, exhibiting significant conformational dynamics.
- The specific base pairing within the loops critically influences the overall structure and dynamics, particularly glycosidic bond configuration.
- In contrast, r(G2C4)exp repeats, forming 2x2 CC/CC loops, display markedly reduced dynamics.
- r(G4C2)exp shows a unique sensitivity to subtle changes in stacking interactions, a property not observed in r(G2C4)exp.
Conclusions:
- The conformational dynamics of r(G4C2)exp loops are highly sensitive to sequence and structural nuances.
- These findings highlight distinct dynamic behaviors between r(G4C2)exp and r(G2C4)exp repeats.
- Understanding this sensitivity provides crucial insights for developing structure-based therapeutic strategies for c9ALS/FTD.
