Abstract
Autophagy is an intracellular lysosomal degradation process induced under stress conditions. Autophagy also plays a major role in ocular patho-physiology. Molecular aging does occur in the trabecular meshwork, the main regulator of aqueous humor outflow, and trabecular meshwork senescence is accompanied by increased oxidative stress. However, the role of autophagy in trabecular meshwork patho-physiology has not yet been examined in vivo in human ocular tissues. The purpose of the herein presented study is to evaluate autophagy occurrence in ex-vivo collected human trabecular meshwork specimens and to evaluate the relationship between autophagy, oxidative stress, and aging in this tissue. Fresh trabecular meshwork specimens were collected from 28 healthy corneal donors devoid of ocular pathologies and oxidative DNA damage, and LC3 and p62 protein expression analyzed. In a subset of 10 subjects, further to trabecular meshwork proteins, the amounts of cathepesin L and ubiquitin was analyzed by antibody microarray in aqueous humor. Obtained results demonstrate that autophagy activation, measured by LC3II/I ratio, is related with. oxidative damage occurrence during aging in human trabecular meshwork. The expression of autophagy marker p62 was lower in subjects older than 60 years as compared to younger subjects. These findings reflect the occurrence of an agedependent increase in the autophagy as occurring in the trabecular meshwork. Furthermore, we showed that aging promotes trabecular-meshwork senescence due to increased oxidative stress paralleled by autophagy increase. Indeed, both oxidative DNA damage and autophagy were more abundant in subjects older than 60 years. These findings shed new light on the role of oxidative damage and autophagy during trabecular-meshwork aging.
Highlights
Autophagy is a highly conserved housekeeping pathway that plays a critical role in the removal of aged or damaged intracellular organelles and their delivery to lysosomes for degradation, [1,2]
Protein expression of LC3I, LC3II, and p62 in the trabecular meshwork (TM) were analysed by Western blot
Inflammation, and accumulation of protein-rich deposits occur both in TM endothelium and in retinal pigment epithelium heralding the onset of age-related degeneration
Summary
Autophagy is a highly conserved housekeeping pathway that plays a critical role in the removal of aged or damaged intracellular organelles and their delivery to lysosomes for degradation, [1,2]. There are three major autophagic pathways that have been described, microautophagy, chaperone-mediated autophagy, and macroautophagy. The final step of autophagy involves the fusion of the autophagosome with the lysosome to form the autophagolysosome, in which the gathered cargo is degraded by lysosomal hydrolases. It has been described the role of p53 tumor suppressor protein in regulating autophagy. Depending on the p53 location, this protein exerts distinct and important function Regarding this dual role, nuclear p53 acts as a transcription factor to stimulate both DRAM1 and Sestrin 2, which in turns switch on autophagy. In order to induce autophagy, p53 is degraded through proteosomes, [4]
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