Cyclic mismatch binding ligands interact with disease-associated CGG trinucleotide repeats in RNA and suppress their...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to CGG repeat expansion in the FMR1 gene.
• Neuron degeneration in FXTAS is associated with the accumulation of polyglycine protein (FMRpolyG), arising from translation upstream of the repeats.

Purpose of the Study:

• To investigate if naphthyridine-based molecules can inhibit FMRpolyG synthesis by targeting CGG repeats in RNA.
• To determine if these molecules can reverse pathological changes in affected cells and preserve FMRP levels.
• To evaluate the therapeutic potential of CMBL4c in FXTAS cell models.

Main Methods:

• Utilized cyclic mismatch binding ligand CMBL4c to target RNA structures formed by CGG repeats.
• Assessed the impact of CMBL4c on FMRpolyG translation and nuclear inclusion formation in transfected cells.
• Evaluated CMBL4c's effects on FMRpolyG-mediated cytotoxicity, apoptosis, and FMRP levels.

Main Results:

• CMBL4c successfully binds to CGG repeat RNA structures, attenuating FMRpolyG translation and reducing nuclear inclusions.
• CMBL4c treatment decreased FMRpolyG-induced cytotoxicity and apoptosis, demonstrating therapeutic potential even after inclusion formation.
• FMRpolyG reduction by CMBL4c was associated with a partial decrease in FMRP levels.

Conclusions:

• CMBL4c exhibits therapeutic potential for FXTAS by inhibiting toxic FMRpolyG production and mitigating associated cellular damage.
• The observed partial FMRP reduction necessitates further investigation into CMBL4c's efficacy and safety in differentiated tissues for FXTAS treatment.