RNA G‑Quadruplex Reprogramming with Guanine-Rich Antisense Oligonucleotides Inhibits Monoamine Oxidase B's...

Area of Science:

• Molecular Biology
• RNA Structure and Function
• Neuroscience

Background:

• The human transcriptome features RNA G-quadruplexes (rG4s) that regulate gene expression, including translation, via ribosome stalling.
• Canonical rG4s in mRNA 5' untranslated regions (5'UTRs) can impede translation, a mechanism implicated in neurodegenerative diseases like Parkinson's disease (PD).
• The role of rG4s in non-mutated therapeutic targets, such as monoamine oxidase B (MAOB), remains largely uncharacterized.

Purpose of the Study:

• To identify and characterize an rG4 in the 5'UTR of MAOB mRNA.
• To investigate methods for modulating this rG4 to control MAOB translation.
• To explore the therapeutic potential of targeting rG4s for conditions like PD.

Main Methods:

• Identification of an rG4 in the MAOB mRNA 5'UTR.
• In vitro and in cellulo assays to assess rG4 translation inhibition.
• Stabilization of the rG4 using the PhenDC3 ligand.
• Reprogramming the rG4 using G-rich antisense oligonucleotides (G-ASOs) to alter its structure and function.

Main Results:

• An rG4 was identified in the MAOB mRNA 5'UTR, demonstrating translation inhibitory effects in vitro and in cellulo.
• The translation inhibition was enhanced by the PhenDC3 ligand.
• G-ASOs (DNA or 2'OMe) induced a new intermolecular rG4 folding, specifically reducing MAOB translation in vitro and in cellulo.

Conclusions:

• rG4s in MAOB mRNA 5'UTR can be modulated to control protein synthesis.
• G-ASOs offer a targeted approach to reprogram rG4s, offering specificity compared to ligands.
• This strategy of rG4 modulation via G-ASOs presents a novel therapeutic avenue for reducing MAOB activity and potentially alleviating PD symptoms.