Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• De novo mutations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) are linked to severe childhood-onset neurodegenerative disorders.
• The precise molecular mechanisms by which IRF2BPL loss leads to neural dysfunction remain largely unknown.

Purpose of the Study:

• To elucidate the function of IRF2BPL in neural development and disease.
• To investigate the role of Wnt signaling in IRF2BPL-associated neurodegeneration.

Main Methods:

• Utilized Drosophila and zebrafish models to study IRF2BPL function.
• Examined gene expression, protein interactions, and utilized pharmacological inhibition of Wnt signaling.
• Analyzed patient-derived astrocytes.

Main Results:

• IRF2BPL and its Drosophila ortholog Pits repress Wnt transcription.
• Neuronal depletion of Pits in Drosophila increases wingless (wg) levels and causes axonal loss; Wnt inhibition is neuroprotective.
• Loss of irf2bpl in zebrafish results in neurological defects and increased wnt1 signaling.
• WNT1 is elevated in patient astrocytes, and Wnt inhibition ameliorates neurological phenotypes.
• IRF2BPL interacts with CKIα, indicating a shared role in antagonizing Wnt signaling.

Conclusions:

• IRF2BPL functions as a repressor of Wnt signaling, and its loss leads to neurodegenerative phenotypes through Wnt pathway dysregulation.
• Targeting the Wnt signaling pathway presents a potential therapeutic strategy for IRF2BPL-related neurodegenerative disorders.