An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome
Pratibha Thakur1, Martin Lackinger1,2, Anastasia Diamantopoulou1
1Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States.
Elife
|May 27, 2025
Summary
This study reveals that elevated EMC10 levels contribute to 22q11.2 Deletion Syndrome. Reducing EMC10 in neurons and mouse models improves cognitive and neural deficits, showing therapeutic potential.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- 22q11.2 Deletion Syndrome (22q11.2DS) is linked to cognitive, social, and emotional impairments, with a high risk of schizophrenia.
- MicroRNA dysregulation is implicated in 22q11.2DS, leading to the upregulation of EMC10, a protein involved in membrane protein insertion.
- Previous work identified EMC10's role in the behavioral phenotypes of 22q11.2DS mouse models.
Purpose of the Study:
- To investigate the role of EMC10 in neurons from 22q11.2DS carriers.
- To assess the therapeutic potential of normalizing EMC10 levels in 22q11.2DS.
Main Methods:
- Analyzed miRNA expression and EMC10 levels in neurons derived from 22q11.2DS carriers.
- Reduced EMC10 levels in patient-derived neurons to assess effects on neurite outgrowth and calcium signaling.
- Administered antisense oligonucleotides to normalize Emc10 in adult mouse brains to evaluate cognitive function.
Main Results:
- Abnormal miRNA processing and elevated EMC10 expression were observed in 22q11.2DS patient-derived neurons.
- Reducing EMC10 levels in these neurons restored normal neurite outgrowth and calcium signaling.
- Normalization of Emc10 in adult mice significantly improved cognitive deficits in social and spatial memory, with sustained effects.
Conclusions:
- EMC10 plays a critical role in the pathophysiology of 22q11.2 Deletion Syndrome.
- Modulating EMC10 levels offers a promising therapeutic strategy for ameliorating cognitive and neural deficits in 22q11.2DS.
- This study bridges findings from animal models and human neurons, highlighting the translational potential of targeting EMC10.
Keywords:
22q11.2 deletionEMC10antisense oligonucleotideshumanhuman iPSCmiRNA dysregulationmouseneuroscienceprecision psychiatryschizophreniaMore Related Videos
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