Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell models
Related Experiment Video
Updated: Aug 29, 2025
In Vitro Modeling of Down Syndrome Neurogenesis Using Human-Induced Pluripotent Stem Cells
Published on: March 7, 2025
Sara G Susco1, Sulagna Ghosh2, Patrizia Mazzucato2
1Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Abstract:
Down syndrome (DS), driven by an extra copy of chromosome 21 (HSA21), and fragile X syndrome (FXS), driven by loss of the RNA-binding protein FMRP, are two common genetic causes of intellectual disability and autism. Based upon the number of DS-implicated transcripts bound by FMRP, we hypothesize that DS and FXS may share underlying mechanisms. Comparing DS and FXS human pluripotent stem cell (hPSC) and glutamatergic neuron models, we identify increased protein expression of select targets and overlapping transcriptional perturbations. Moreover, acute upregulation of endogenous FMRP in DS patient cells using CRISPRa is sufficient to significantly reduce expression levels of candidate proteins and reverse 40% of global transcriptional perturbations. These results pinpoint specific molecular perturbations shared between DS and FXS that can be leveraged as a strategy for target prioritization; they also provide evidence for the functional relevance of previous associations between FMRP targets and disease-implicated genes.
Insights
Down syndrome and fragile X syndrome share molecular mechanisms, suggesting common therapeutic targets. Restoring FMRP in Down syndrome cells partially reversed disease-related gene expression changes.
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.
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