Abstract
Glaucoma is a progressive optic neuropathy characterized by axonal degeneration and retinal ganglion cells loss. Several factors have been postulated to play a role in glaucoma, elevated intraocular pressure (IOP) being the best well-known causative factor. The mechanisms leading to ocular hypertension and glaucoma are still not fully understood. An increasing number of evidence indicates a role of autophagy in the pathophysiological process of ocular hypertension and glaucoma. However, while all of the studies agree that autophagy is induced in RGCs in response to injury, autophagy was found to either protect or promote cell death depending on the experimental model used. In order to gain more insight into both, the role of autophagy in the pathogenesis of glaucoma and the effect of chronic IOP elevation in the autophagy pathway, we have investigated here for the first time autophagy in the iridocorneal angle region, retinal ganglion cell bodies, and ON axons in the spontaneous ocular hypertensive DBA/2J mouse glaucoma model and in the transgenic DBA/2J::GFP-LC3 mice, generated in our laboratory. Our results indicate decreased autophagic flux in the outflow pathway cells in the DBA/2J mice, characterized by increased levels of LC3-II and p62 together with a decrease in the lysosomal marker LAMP1, evaluated by western blot and immunofluorescence. Elevated presence of autophagic vacuoles in the DBA/2J and, in particular, in the DBA/2J::GFP-LC3 mice was also observed. Expression of the GFP-LC3 transgene was associated to higher cumulative IOP in the DBA/2J background. In addition to higher elevation in IOP, DBA/2J::GFP-LC3 were characterized by further RGCs and exacerbated axonal degeneration compared to DBA/2J. This was accompanied by the notable high presence of autophagic figures within degenerating axons. These results strongly suggest overactivation of autophagy as a potential cellular mechanism leading to ON degeneration in the chronic hypertensive DBA/2J mice.
Highlights
Glaucoma is a progressive optic neuropathy, second leading cause of permanent blindness worldwide
Elevated intraocular pressure (IOP) results from the failure of the trabecular meshwork (TM)/Schlemm’s canal (SC) conventional outflow pathway, a tissue located in the anterior segment of the eye, to maintain appropriate levels of aqueous humor (AH) outflow resistance[3]
This is the first and only comprehensive study investigating the occurrence of autophagy in all the ocular tissues involved in the pathogenesis of hypertensive glaucoma
Summary
Glaucoma is a progressive optic neuropathy, second leading cause of permanent blindness worldwide. Several factors have been postulated to play a role in glaucoma including ischemia excitotoxicity, neurotrophic insufficiency, and elevated intraocular pressure (IOP). Among them, elevated IOP remains the best-established causative factor[1,2]. Elevated IOP results from the failure of the trabecular meshwork (TM)/Schlemm’s canal (SC) conventional outflow pathway, a tissue located in the anterior segment of the eye, to maintain appropriate levels of aqueous humor (AH) outflow resistance[3]. The exact mechanisms by which elevated IOP triggers axonal degeneration and retinal ganglion cell (RGC) death is currently unknown. IOP-related mechanical injury to the optic nerve (ON) head at the lamina cribrosa level might lead to ischemia-hypoxia damage, blockage of Official journal of the Cell Death Differentiation Association
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
