Bim Inhibition Ameliorates Visual Loss and Promotes Axon Regeneration by Up-Regulation of Drd1 Expression

Area of Science:

• Neuroscience
• Ophthalmology
• Cell Biology

Background:

• Retinal ganglion cell (RGC) degeneration is a major cause of vision loss.
• The pro-apoptotic molecule Bim (Bcl-2-interacting mediator of cell death) plays a role in RGC death after injury.
• Developing strategies to inhibit Bim could offer neuroprotection for RGCs.

Purpose of the Study:

• To evaluate the neuroprotective effects of inhibiting Bim in RGCs using a mouse optic nerve crush (ONC) model.
• To investigate the role of Bim in RGC survival and axonal integrity following ONC.
• To explore the underlying molecular mechanisms, including Drd1 signaling, associated with Bim inhibition.

Main Methods:

• Established a mouse ONC model to induce RGC degeneration.
• Administered AAV2-shBim via intravitreal injection to inhibit Bim expression.
• Assessed RGC survival, retinal structure, visual function, and axonal preservation using immunohistochemistry, RBPMS immunofluorescence, optical coherence tomography, electroretinography, and CTB-555 tracing.
• Utilized dorsal root ganglion (DRG) neuron cultures to study axon growth.
• Performed RNA sequencing, qPCR, and pharmacological modulation of Drd1 signaling.

Main Results:

• ONC led to increased Bim expression and significant RGC loss.
• AAV2-shBim treatment reduced Bim, preserved retinal structure, enhanced RGC survival, and improved visual function and axonal preservation.
• Bim knockdown promoted axon growth in DRG cultures, while overexpression inhibited it.
• Bim inhibition upregulated Drd1 expression, and DRD1 activation enhanced axon growth.

Conclusions:

• Inhibiting Bim provides neuroprotection to RGCs and promotes axonal preservation after ONC.
• Drd1-related signaling pathways may contribute to the observed neuroprotective effects of Bim inhibition.
• Targeting Bim represents a potential therapeutic strategy for conditions involving RGC damage and vision loss.