Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell...

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Down syndrome (DS) and fragile X syndrome (FXS) are leading genetic causes of intellectual disability and autism.
• DS results from trisomy of chromosome 21 (HSA21), while FXS stems from FMRP protein loss.
• Shared molecular pathways between DS and FXS remain largely unexplored.

Purpose of the Study:

• To investigate shared molecular mechanisms between DS and FXS.
• To identify common molecular targets for therapeutic intervention.
• To explore the role of FMRP in DS-related gene expression.

Main Methods:

• Comparative analysis of DS and FXS models using human pluripotent stem cells (hPSCs) and glutamatergic neurons.
• Assessment of protein expression and transcriptional profiles.
• CRISPR activation (CRISPRa) to upregulate FMRP in DS patient cells.

Main Results:

• Identified overlapping transcriptional perturbations and increased protein expression of select targets in both DS and FXS models.
• Demonstrated that acute FMRP upregulation in DS cells significantly reduced candidate protein levels.
• Showed FMRP upregulation reversed 40% of global transcriptional perturbations in DS cells.

Conclusions:

• DS and FXS share specific molecular perturbations, offering a basis for target prioritization.
• FMRP plays a functional role in regulating genes implicated in DS.
• These findings support the therapeutic potential of targeting FMRP-related pathways in both syndromes.