Retinoid X receptor alpha overexpression protects retinal ganglion cells and modulates inflammatory response in experimental glaucoma

Glaucoma is characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve axons, and its risk increases with age. Retinal neuroinflammation and epigenetic changes have been suggested to be key contributors to glaucoma neuropathology. Recent research suggests that activating the retinoid X receptor (RXR) in the retina plays a critical role in modulating various cellular functions, showcasing beneficial effects in animal models of glaucoma. Yet, the neuroprotective mechanisms activated in response to RXR modulation in glaucoma remain unclear. This study investigated the impact of RXR alpha (RXRα) modulation on retinal neurons in vivo under both normal and glaucoma conditions using adeno-associated virus (AAV) gene therapy. RXRα knockdown in RGCs promoted histone deacetylation, pro-inflammatory, and apoptotic changes, along with inducing functional and structural deficits in the inner retina. In contrast, overexpression of RXRα in RGCs protected these cells and preserved inner retinal function in glaucoma through the activation of PI3K/Akt/Gsk3β signaling. This study identified the RXRα-mediated epigenetic and inflammatory regulatory mechanisms in RGCs and established that specifically targeting RXRα in RGCs imparts functional and cellular protection to the retina in glaucoma, with potential implications in other neurodegenerative disorders.