The autophagic lysosomal system in outflow pathway physiology and pathophysiology

Abstract

Malfunction of the trabecular meshwork (TM)/schlemm’s canal (SC) conventional outflow pathway is associated with elevated intraocular pressure (IOP) and, therefore, increased risk of developing glaucoma, a potentially blinding disease affecting more than 70 million people worldwide. This TM/SC tissue is subjected to different types of stress, including mechanical, oxidative, and phagocytic stress. Long-term exposure to these stresses is believed to lead to a progressive accumulation of damaged cellular and tissue structures causing permanent alterations in the tissue physiology, and contribute to the pathologic increase in aqueous humor (AH) outflow resistance. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors. In addition to performing basal functions, autophagy acts as a cellular survival pathway and represents an essential mechanism by which organisms can adapt to acute stress conditions and repair stress-induced damage. A decline in autophagy has been observed in most tissues with aging and has been considered responsible, at least in part, for the accumulation of damaged cellular components in almost all tissues of aging organisms. Dysfunction in the autophagy pathway is associated with several human diseases, from infectious diseases to cancer and neurodegeneration. In this review, we will summarize our current knowledge of the emerging roles of autophagy in outflow tissue physiology and pathophysiology, including novel evidence suggesting compromised autophagy in the glaucomatous outflow pathway.

Working your SOCS off: The role of ASB10 and protein degradation pathways in glaucoma

“…The UPS and AL protein degradation pathways are functional in healthy cells of both the TM and the retina (Esteve-Rudd et al, 2010; Liton, 2016; Liton et al, 2009a; Munemasa and Kitaoka, 2015). Evidence is accumulating that dysfunction of these pathways in aged and glaucomatous tissues may lead to accumulation of toxic material and a progressive cellular decline of cellular function (Caballero et al, 2004; Liton et al, 2009c).…”

“…These have been extensively reviewed elsewhere so we shall only provide a brief overview of their findings (Liton, 2016; Liton et al, 2009a; Qiu et al, 2014; Sirohi and Swarup, 2016; Ying and Yue, 2016). All of these studies suggest that the pathways work in tandem to clear proteins from cells.…”

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

“…Due to high levels of fluctuations in IOP from blinking, eye movement and ocular pulse, TM cells are constantly under mechanical forces and strain (9, 14, 15). TM cells react to this stress, by maintaining cellular and tissue homeostasis, and preventing injury (16, 17). Strain causes profound changes to cell morphology, affecting motility, stiffness, contraction, orientation, and cell alignment (14-16).…”

“…TM cells react to this stress, by maintaining cellular and tissue homeostasis, and preventing injury (16, 17). Strain causes profound changes to cell morphology, affecting motility, stiffness, contraction, orientation, and cell alignment (14-16). Recent studies have indicated autophagy as one of the relevant stress response adaptive mechanisms (16, 18, 19).…”

Major review: Molecular genetics of primary open-angle glaucoma

“…Multiple genetic and molecular studies indicate the important contribution of autophagy to the pathogenesis of POAG (Frost et al, 2014; Hirt and Liton, 2017; Liton, 2016; Minegishi et al, 2016; Porter et al, 2015; Porter et al, 2013; Porter et al, 2014; Slowicka et al, 2016; Tucker et al, 2014; Wong and Holzbaur, 2014). As discussed earlier, a number of genetic factors are involved in or associated with the pathogenesis of POAG.…”