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.
Highlights
Glaucoma is a neurodegenerative disease characterized by physiological intraocular hypertension and the progressive death of retinal ganglion cells (RGCs) [1,2]
We demonstrated that autophagy, aside from apoptosis alone, was activated in the RGC of a rhesus monkey model of chronic ocular hypertension using different methods suitable for studying autophagic flux in vivo
The extent and pattern of RGC deficits have been reported to mimic those of humans in the experimental glaucoma model of the rhesus monkey [27,28], and apoptosis has been suggested as the final pathway for RGC loss in chronic glaucoma for several decades [1,31]
Summary
Glaucoma is a neurodegenerative disease characterized by physiological intraocular hypertension and the progressive death of retinal ganglion cells (RGCs) [1,2]. Several recent studies have reported that autophagy is activated in RGCs and plays a role in autophagic cell death after IOP elevation [5,6,7,8]. The autophagosome fuses with lysosomal vesicles to degrade the cargo contents, forming an autolysosome [9,10,11] Through this stepwise maturation process, autophagy delivers long-lived proteins or unwanted organelles into the lysosome for degradation and reuses the resulting amino acids, maintaining the quality control of essential cellular components as well as of cellular homeostasis [11]. Deficiencies in lysosomal membrane proteins, i.e., LAMPs, can disturb autophagosome maturation, resulting in increased amounts of AVi or both AVi and AVd [9,15] This observed relationship indicates that an estimation of the formation of AVi and AVd and the lysosomal membrane proteins approximates whether the autophagic flux is increased or reduced
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