Abstract
Glaucoma is leading cause of blindness worldwide, which is characterized by progressive optic neuropathy and degeneration of retinal ganglion cells (RGCs), one of the retinal neurons transmits visual information to the brain. Because RGC degeneration is one of the hall marks of the disease, many studies have paid attention to only neurons. In this symposium, we report that impaired glial function triggers pathogenesis of normal-tension glaucoma. We have recently discovered that astrocyte dysfunction by lacking ATP-binding cassette transporter A1 (ABCA1) causes glaucoma-like phenotypes. The astrocyte-specific ABCA1KO (Astro-KO) mice showed RGC degeneration and visual impairment at 12 months old without changes in an intraocular pressure, a conventional glaucoma risk factor which can cause damages in RGCs. To further clarifying the molecular mechanisms, we performed bulk and single-cell RNA-sequence of retina. We found that RGCs and retinal astrocytes up-regulate neuroinflammatory pathways including CXCR4 and CCR5 signaling. CXCL12 and CCL5 were up-regulated in astrocytes in vitro and in vivo. Because CXCR4 and CCR5 were highly expressed in RGCs, the astrocyte-derived chemokines might affect RGC functions. We identified a novel RGC subclass enriched in a unique set of NMDA subunit genes, implicating higher sensitivity to excitotoxicity. Supporting this, intravitreal NMDA injection caused exacerbated RGC damages in Astro-KO mice. Thus, our data demonstrate that astrocytic dysfunction causes non-cell-autonomous optic neuropathy.
