ABSTRACT
Title
The role of autophagy in Retinal Ganglion Cell death: new perspective for retinal neuroprotection
Authors
R. Russo1 , M.T. Corasaniti2 and G. Bagetta1
1Department of Pharmacobiology, University of Calabria, Rende (CS), Italy and 2Department of Pharmacobiological Sciences, University Magna Graecia, Catanzaro, Italy
1Department of Pharmacobiology, University of Calabria, Rende (CS), Italy and 2Department of Pharmacobiological Sciences, University Magna Graecia, Catanzaro, Italy
Abstract
Glaucoma is a group of optic neuropathies characterized by the alteration of the optic nerve and the death of retinal ganglion cells (RGCs) and represents one of the leading causes of irreversible blindness.The structures affected in glaucoma, retina and optic nerve, are part of the central nervous system (CNS), therefore, glaucoma is considered, under every respect, a neurodegenerative disorder, sharing mechanisms of cell damage and loss with central diseases.
Autophagy is the major intracellular degradation pathway by which eukaryotic cells regulate the turnover of long-lived proteins and organelles. In recent years the connection between autophagy and neurodegeneration has been strengthened by several studies underlying the vulnerability of neurons to stress-related signals that impair the autophagic process and increasing attention has been focused on the role of autophagy in neuronal cell death associated with acute neuronal injury and chronic neurodegenerative disorders.
However, despite the numerous studies on the role of autophagy in various neurodegenerative diseases, the autophagic process in RGCs exposed to stressor stimuli has not yet been investigated.
We recently aimed to study the dynamic of the autophagic process in the retina following by transient ischemia, a common feature of ocular pathologies including glaucoma, anterior ischemic optic neuropathy and retinal vessels occlusion. Retinal ischemia was associated with a reduction of the autophagosome-associated form of LC3 (LC3II) and with a significant decrease of beclin-1 expression, a protein involved in the early steps of autophagy vesicle formation. The latter event was paralleled by the calpain-mediated proteolytic cleavage of beclin-1. Furthermore, inhibition of autophagy in immortalized RGCs worsened cell loss under serum starvation conditions.
Our findings provided evidence of autophagy deregulation in the retina under ischemic insult, support a neuroprotective role of autophagy in RGCs and suggest that excitotoxicity, occurring under retinal ischemia, negatively regulates autophagy through the calpain-mediated cleavage of Beclin-1.
The further comprehension of the modulation of the autophagic pathway under physiological and pathological conditions in the retina and the optic nerve might lead to significant advances in the knowledge of the mechanisms underlying neurodegeneration occurring in glaucoma and would offer new hubs for the development of novel neuroprotective therapeutic approaches.
Autophagy is the major intracellular degradation pathway by which eukaryotic cells regulate the turnover of long-lived proteins and organelles. In recent years the connection between autophagy and neurodegeneration has been strengthened by several studies underlying the vulnerability of neurons to stress-related signals that impair the autophagic process and increasing attention has been focused on the role of autophagy in neuronal cell death associated with acute neuronal injury and chronic neurodegenerative disorders.
However, despite the numerous studies on the role of autophagy in various neurodegenerative diseases, the autophagic process in RGCs exposed to stressor stimuli has not yet been investigated.
We recently aimed to study the dynamic of the autophagic process in the retina following by transient ischemia, a common feature of ocular pathologies including glaucoma, anterior ischemic optic neuropathy and retinal vessels occlusion. Retinal ischemia was associated with a reduction of the autophagosome-associated form of LC3 (LC3II) and with a significant decrease of beclin-1 expression, a protein involved in the early steps of autophagy vesicle formation. The latter event was paralleled by the calpain-mediated proteolytic cleavage of beclin-1. Furthermore, inhibition of autophagy in immortalized RGCs worsened cell loss under serum starvation conditions.
Our findings provided evidence of autophagy deregulation in the retina under ischemic insult, support a neuroprotective role of autophagy in RGCs and suggest that excitotoxicity, occurring under retinal ischemia, negatively regulates autophagy through the calpain-mediated cleavage of Beclin-1.
The further comprehension of the modulation of the autophagic pathway under physiological and pathological conditions in the retina and the optic nerve might lead to significant advances in the knowledge of the mechanisms underlying neurodegeneration occurring in glaucoma and would offer new hubs for the development of novel neuroprotective therapeutic approaches.