Targeting circular RNA-Glra2 alleviates retinal neurodegeneration induced by ocular hypertension

Glaucoma is a leading cause of irreversible vision loss characterized by retinal neurodegeneration. Circular RNAs (circRNAs) have emerged as the potential biomarkers and therapeutic targets for neurodegenerative diseases. However, the expression profiling of circRNAs in glaucomatous neurodegeneration has not been fully understood. In this study, we built a glaucomatous neurodegeneration model via the injection of microbeads into anterior chamber. circRNA expression profile and bioinformatics analysis revealed that compared with normal retinas, 171 circRNAs were dysregulated in the glaucomatous retinas, including 101 up-regulated circRNAs and 70 down-regulated circRNAs. Detecting the level of circular RNA-glycine receptor α2 subunit gene (cGlra2) in aqueous humor made it possible to distinguish glaucoma patients from cataract patients. Silencing of cGlra2 protected against oxidative stress- or hydrostatic pressure-induced retinal ganglion cell (RGC) injury in vitro. Moreover, silencing of cGlra2 retarded ocular hypertension-induced retinal neurodegeneration in vivo as shown by increased TUJ1 staining, reduced reactive gliosis, decreased retinal cell apoptosis, enhanced visual acuity, and improved retinal function. cGlra2 acted as a miRNA sponge to regulate RGC function through cGlra2/miR-144/BCL2L11 signaling axis. Collectively, this study provides novel insights into the underlying mechanism of retinal neurodegeneration and highlights the potential of cGlra2 as a target for the diagnosis and treatment of glaucoma.