Autophagy in Retinal Ganglion Cells in a Rhesus Monkey Chronic Hypertensive Glaucoma Model

Abstract

Primary open angle glaucoma (POAG) is a neurodegenerative disease characterized by physiological intraocular hypertension that causes damage to the retinal ganglion cells (RGCs). In the past, RGC damage in POAG was suggested to have been attributed to RGC apoptosis. However, in the present study, we applied a model closer to human POAG through the use of a chronic hypertensive glaucoma model in rhesus monkeys to investigate whether another mode of progressive cell death, autophagy, was activated in the glaucomatous retinas. First, in the glaucomatous retinas, the levels of LC3B-II, LC3B-II/LC3B-I and Beclin 1 increased as demonstrated by Western blot analyses, whereas early or initial autophagic vacuoles (AVi) and late or degraded autophagic vacuoles (AVd) accumulated in the ganglion cell layer (GCL) and in the inner plexiform layer (IPL) as determined by transmission electron microscopy (TEM) analysis. Second, lysosome activity and autophagosome-lysosomal fusion increased in the RGCs of the glaucomatous retinas, as demonstrated by Western blotting against lysosome associated membrane protein-1 (LAMP1) and double labeling against LC3B and LAMP1. Third, apoptosis was activated in the glaucomatous eyes with increased levels of caspase-3 and cleaved caspase-3 and an increased number of TUNEL-positive RGCs. Our results suggested that autophagy was activated in RGCs in the chronic hypertensive glaucoma model of rhesus monkeys and that autophagy may have potential as a new target for intervention in glaucoma treatment.

New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system

“…Autophagy was induced in a chronic hypertensive glaucoma model induced by laser photocoagulation in primates (Deng et al, 2013) and increased number of autophagosomes and of autophagy related proteins, LC3II and beclin-1, were detected in soma and dendrites of RGCs from rats subjected to episcleral vein cauterization (Park et al, 2012). In the latter study, pharmacological inhibition of autophagy by 3-MA increased cell survival in the ganglion cell layer suggesting a protective role for autophagy (Park et al, 2012).…”

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

“…Park et al [46,51] reported that the activation of autophagy results in the apoptosis of RGCs in a chronic glaucoma model. Although autophagy and apoptosis can coexist in the same damaged RGC, they do not necessarily overlap and can occur independently [58,92]. Autophagy can occur before neuronal apoptosis in aluminum-insulted astrocytes, a chronic hypertensive glaucoma model, and an optic nerve axotomy mouse model [46,93,94].…”

Autophagy dysregulation and the fate of retinal ganglion cells in glaucomatous optic neuropathy

“…Deng and colleagues found that autophagy was activated in a chronic hypertensive glaucoma model induced by laser photocoagulation in rhesus monkeys; the enhanced autophagic flux was demonstrated by the increase of LC3II, LC3II/LC3I ratio, and beclin-1 together with the accumulation of autophagic vacuoles and the upregulation of lysosomal activity (Deng et al, 2013). Similarly, Kitaoka and coauthors observed the presence of autophagic vacuoles in unmyelinated axons 3 weeks after IOP elevation induced by laser photocoagulation in rats (Kitaoka et al, 2013).…”