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Bim Inhibition Ameliorates Visual Loss and Promotes Axon Regeneration by Up-Regulation of Drd1 Expression
Zhenhao Cheng1, Lingling Wu2, Yilun Qu2
1Senior Department of Ophthalmology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China; Medical School of Chinese PLA, Beijing, China.
Abstract:
This study evaluated the neuroprotective effects of Bim (Bcl-2-interacting mediator of cell death) inhibition in retinal ganglion cells (RGCs) after optic nerve crush (ONC). Bim expression and RGC survival were assessed by immunohistochemistry, RNA-binding protein with multiple splicing (RBPMS) immunofluorescence, and histologic analyses. Following intravitreal injection of adeno-associated virus serotype 2-shRNA targeting Bim (shBim), retinal structure and visual function were evaluated by optical coherence tomography, flash visual-evoked potentials, and flash electroretinography. Optic nerve axons were assessed by cholera toxin subunit B-555 anterograde tracing. Primary dorsal root ganglion neurons were used to examine the effects of Bim manipulation on axon growth. RNA sequencing, quantitative RT-PCR, and pharmacologic dopamine receptor D1 (DRD1) modulation were performed to investigate downstream molecular changes. ONC markedly elevated Bim expression alongside substantial RGC loss. Adeno-associated virus serotype 2-shBim treatment reduced Bim expression, preserved retinal structure, increased RGC survival, partially improved visual function, and enhanced axonal preservation after injury. In dorsal root ganglion neuron cultures, Bim knockdown promoted axon elongation, whereas Bim overexpression suppressed axon growth. Transcriptomic analysis and quantitative PCR revealed up-regulation of Drd1 following Bim inhibition. Pharmacologic activation of DRD1 promoted axon growth, whereas DRD1 blockade attenuated this effect. Taken together, these findings indicate that Bim inhibition promotes RGC survival and axonal preservation after ONC, with Drd1-related signaling potentially contributing to these effects.
Insights
Inhibiting the pro-apoptotic molecule Bim (Bcl-2-interacting mediator of cell death) protected retinal ganglion cells after optic nerve injury. This neuroprotection involved enhanced survival and axonal preservation, potentially through Drd1 signaling pathways.
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.