Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection

Abstract

Glaucoma, which affects more than 70 million people worldwide, is a heterogeneous group of disorders with a resultant common denominator; optic neuropathy, eventually leading to irreversible blindness. The clinical manifestations of primary open-angle glaucoma (POAG), the most common subtype of glaucoma, include excavation of the optic disc and progressive loss of visual field. Axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies are observed in glaucoma, in which the reduction of intraocular pressure (IOP) is known to slow progression of the disease. A pattern of localized retinal nerve fiber layer (RNFL) defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. The mechanisms of degeneration of neuronal cell bodies and their axons may differ. In this review, we addressed the molecular mechanisms of cell body death and axonal degeneration in glaucoma and proposed axonal protection in addition to cell body protection. The concept of axonal protection may become a new therapeutic strategy to prevent further axonal degeneration or revive dying axons in patients with preperimetric glaucoma. Further study will be needed to clarify whether the combination therapy of axonal protection and cell body protection will have greater protective effects in early or progressive glaucomatous optic neuropathy (GON).

Keywords: axonal degeneration; axonal protection; glaucoma; optic nerve; retinal ganglion cell.

Figure 1

Localization of Trx1 in the optic nerve. (A) and (B) Double staining for Trx1 (green) and neurofilament (red). Substantial co-localization of Trx1 and NF is observed in the PBS-treated optic nerve. (C) Double staining for trx1 (green) and vimentin (red). No colocalization of Trx1 and Vimentin is observed in the PBS-treated optic nerve. Scale bar, 25 μm. Trx1, trioredoxin1; NF, neurofilament.

Figure 2

Multiple pathogenic and biological mechanisms for glaucomatous neurodegeneration. Increased IOP induces several molecular changes, such as glial activation and release of TNF, mitochondrial dysfunction, degradation of Trx1, NAD, and nmnat1, and obstruction of BDNF transport at lamina area. Molecular changes in the axon cause death signal activation in RGC body, including release of ROS from mitochondria, autoimmune dysregulation, and avtivation of glutamate transporter. TNF, Tumor Necrosis Factor; Trx1, thioredoxin1; NAD, nicotinamide adenine dinucleotide; BDNF, Brain-derived neurotrophic factor; NMDAR, N-methyl-D-aspartate receptor; ER, endoplasmic reticulum.