Related Experiment Video
Updated: May 21, 2025
07:43
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
11.2K
Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency
Anne Gregor1, Laila Distel2, Arif B Ekici2
1Department of Human Genetics, Inselspital University Hospital Bern, University of Bern, 3010 Bern, Switzerland; Department for Biomedical Research (DBMR), University of Bern, 3010 Bern, Switzerland.
HGG Advances
|March 21, 2025
Summary
Haploinsufficiency of FBXO11 causes neurodevelopmental issues. Proteasome-activating drugs, including Verapamil, reversed these phenotypes in human neurons and flies, suggesting potential therapies.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Haploinsufficiency of FBXO11, a ubiquitin ligase subunit, is linked to neurodevelopmental disorders.
- The precise nervous system mechanisms and therapeutic strategies for FBXO11 deficiency remain unclear.
Purpose of the Study:
- To investigate the neurodevelopmental pathomechanisms of FBXO11 deficiency.
- To identify potential therapeutic interventions for FBXO11-related disorders.
Main Methods:
- Established human stem cell-derived neuronal models using CRISPR-Cas9 gene editing.
- Developed Drosophila models with tissue-specific FBXO11 knockdown.
- Conducted transcriptomic analyses (RNA sequencing) and molecular phenotyping.
Main Results:
- FBXO11 deficiency disrupted transcriptional networks crucial for neuronal differentiation, migration, and signaling.
- Observed impaired neuronal migration and proliferation/differentiation balance in human neurons.
- Identified impaired dendritic development and behavioral deficits in Drosophila models.
- Demonstrated that proteasome-activating substances, including Verapamil, ameliorated FBXO11-deficiency phenotypes.
Conclusions:
- FBXO11 is critical for normal neurodevelopment.
- The observed phenotypes associated with FBXO11 deficiency are reversible.
- Drug repurposing, specifically using proteasome activators like Verapamil, offers a promising therapeutic avenue.
