The m⁶A-mediated epi-transcriptomic dysregulation drives synaptic dysfunction in fragile X syndrome

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability, linked to FMR1 gene silencing and FMRP protein loss.
• N6-methyladenosine (m6A) is a key mRNA modification regulating gene expression, and FMRP influences m6A-modified transcripts.
• The impact of FMRP deficiency on transcriptome-wide m6A patterns in FXS was previously unknown.

Purpose of the Study:

• To investigate the role of m6A modifications in FXS pathogenesis.
• To explore the relationship between FMRP deficiency and m6A dysregulation in neuronal function.
• To identify potential therapeutic targets for FXS based on epitranscriptomic mechanisms.

Main Methods:

• Generated induced pluripotent stem cell (iPSC)-derived cortical neurons from FXS patients and healthy controls.
• Performed electrophysiology recordings to assess neuronal and synaptic function.
• Conducted transcriptome-wide m6A analysis and validated molecular mechanisms using genetic manipulation and pharmacological interventions.

Main Results:

• FXS neurons exhibited synaptic and network defects.
• Transcriptome-wide m6A analysis revealed hypermethylation in synapse-associated transcripts in FXS neurons.
• FMRP deficiency caused METTL3 upregulation, driving m6A changes and synaptic defects, which were rescued by METTL3 inhibition or STM-2457 treatment.

Conclusions:

• FMRP deficiency leads to aberrant m6A epitranscriptomic modifications, contributing to FXS pathology.
• METTL3-mediated m6A dysregulation plays a causal role in FXS-related synaptic dysfunction.
• Targeting m6A pathways, such as with METTL3 inhibitors, offers a promising therapeutic strategy for FXS.