A broad perspective on the molecular regulation of retinal ganglion cell degeneration in glaucoma

Abstract

Glaucoma is a complex neurodegenerative disease involving RGC axons, somas, and synapses at dendrites and axon terminals. Recent research advancements in the field have revealed a bigger picture of glaucomatous neurodegeneration that encompasses multiple stressors, multiple injury sites, multiple cell types, and multiple signaling pathways for asynchronous degeneration of RGCs during a chronic disease period. Optic nerve head is commonly viewed as the critical site of injury in glaucoma, where early injurious insults initiate distal and proximal signaling for axonal and somatic degeneration. Despite compartmentalized processes for degeneration of RGC axons and somas, there are intricate interactions between the two compartments and mechanistic overlaps between the molecular pathways that mediate degeneration in axonal and somatic compartments. This review summarizes the recent progress in the molecular understanding of RGC degeneration in glaucoma and highlights various etiological paths with biomechanical, metabolic, oxidative, and inflammatory components. Through this growing body of knowledge, the glaucoma community moves closer toward causative treatment of this blinding disease.

Keywords: Glaucoma; Molecular signaling; Neurodegeneration; Neuroinflammation; Optic nerve axons; Retinal ganglion cells.

FIG. 1

Neurodegeneration in glaucoma involves RGC axons, somas, and synapses at dendrites and axon terminals. The etiological framework of glaucomatous neurodegeneration encompasses multiple stressors (including elevated IOP, aging, genetic, epigenetic, systemic factors), multiple injury sites (optic nerve head, retina, brain), multiple cell types (including glial cells, vascular cells), and multiple signaling pathways for asynchronous degeneration of RGCs during a chronic disease period. A stressor threshold determines the individual susceptibility of RGCs to injury. Optic nerve head is the critical site of injury, and early injury of axons at the optic nerve head can initiate distal and proximal signaling for axonal and somatic degeneration of RGCs. A distal axonopathy is processed by Wallerian degeneration and dying back; however, degeneration of the proximal axon segment appears to be secondary to the apoptosis of RGC soma (that is processed through intrinsic/mitochondrial and extrinsic/dead receptor-mediated pathways). Despite compartmentalized molecular programs for degeneration of RGC axons and somas, there are mechanistic overlaps between the degeneration of RGC axons and somas, which include biomechanical, metabolic, oxidative, and inflammatory components.