Alternate Causes for Pathogenesis of Exfoliation Glaucoma, a Multifactorial Elastotic Disorder: A Literature Review

Abstract

Exfoliation glaucoma (XFG) is the most recognizable form of secondary open-angle glaucoma associated with a high risk of blindness. This disease is characterized by white flaky granular deposits in the anterior chamber that leads to the elevation of intraocular pressure (IOP) and subsequent glaucomatous optic nerve damage. Conventionally, XFG is known to respond poorly to medical therapy, and surgical intervention is the only management option in most cases. Various genetic and nongenetic factors are known to be linked to the development of XFG. Despite decades of research on the genetic factors in exfoliation syndrome (XFS) by study groups and global consortia involving different ethnic populations, the pathogenesis of XFS and the mechanism of onset of glaucoma still remains an unsolved mystery. The key lies in understanding how the function of a gene (or set of genes) is altered by environmental triggers, along with other molecular events that underlie the key disease attributes, namely, oxidative stress and the disruption of the blood–aqueous barrier (BAB). It remains a challenge to evolve a theory encompassing all factions of molecular events occurring independently or parallelly that determine the disease manifestation (phenotype) or the stage of the disease in the eye (or in any tissue) in exfoliation. Our enhanced understanding of the underlying molecular pathophysiology of XFG, beyond the known genes or polymorphisms involved in the disease, will lead to improved diagnosis and management and the ability to recognize how the environment influences these key events that lead to the disease phenotype or disease progression. This review summarizes the recent observations and discoveries of four key factors that may hold the answers to the non-lysyl oxidase-like 1 (LOXL1) mechanisms behind XFG pathogenesis, namely, the epigenetic factor miRNA, disordered autophagy along with the potential involvement of mitochondrial mutations, and a compromised aqueous–blood barrier.

Quantitative analysis of exosomes in the aqueous humor of Korean patients with pseudoexfoliation glaucoma

“…High IOP and/or the use of hypotensive medications may affect the blood-aqueous-barrier, which may further affect the composition of exosomes. However, according to a recent review article, compromised aqueous-blood barrier was also one of mechanisms involved in the pathogenesis of PEX syndrome and PEX glaucoma 29 . PEX syndrome usually does not show high IOP or glaucomatous damage in the optic nerve head.…”

A Feedback Loop between TGF-β1 and ATG5 Mediated by miR-122-5p Regulates Fibrosis and EMT in Human Trabecular Meshwork Cells

“…The reduction of cellular degradative processes, particularly the autophagy–lysosomal pathway, is linked to protein aggregation. We recently discovered that in all stages of XFG, lower unfolded protein response (UPR) clearance is related to elevated TGF levels, implying that the autophagy pathway and TGF-β autophagy crosstalk may be involved in aggregate clearance [ 1 , 7 ]. Autophagy is an intracellular trafficking system that transports cytosolic elements to the lysosome for destruction, which is necessary for misfolded protein clearance, ubiquitin–proteasomal degradation, and cell repair [ 7 , 8 , 9 , 10 , 11 , 12 ].…”

“…We recently discovered that in all stages of XFG, lower unfolded protein response (UPR) clearance is related to elevated TGF levels, implying that the autophagy pathway and TGF-β autophagy crosstalk may be involved in aggregate clearance [ 1 , 7 ]. Autophagy is an intracellular trafficking system that transports cytosolic elements to the lysosome for destruction, which is necessary for misfolded protein clearance, ubiquitin–proteasomal degradation, and cell repair [ 7 , 8 , 9 , 10 , 11 , 12 ]. Autophagy is a protective mechanism that can be triggered by a variety of intracellular and extracellular stimuli, including a lack of amino acids or growth hormones, hypoxia, a low cellular energy status, endoplasmic reticulum stress or oxidative stress, organelle injury, and pathogen infection [ 5 , 7 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Genome-Wide RNA Sequencing of Human Trabecular Meshwork Cells Treated with TGF-β1: Relevance to Pseudoexfoliation Glaucoma

“…Stimulation of normal HTM cells with TGF-β1 modulates pathways and biological processes that show much overlap with processes known to be associated with XFG such as ECM remodelling [ 38 , 39 ], modulation of oxidative stress [ 6 ], UPR [ 40 ] and changes in the expression of certain growth factors [ 14 , 41 , 42 ]. Based on these overlapping findings with XFG expression studies [ 4 , 18 , 43 ] the proposed cellular model could be a useful tool to gain more insight in the pathogenesis of XFG which is still poorly understood [ 1 , 2 , 3 , 44 ]. A comparison of relevant pathways and biological processes between this study and literature is discussed in more detail below.…”

“…The prevalence of XFS is estimated to be 60 million people worldwide, of which half will eventually develop XFG [ 1 ]. The pathogenesis of XFS and progression to XFG have not been fully elucidated [ 1 , 2 , 3 ]. Pathognomonic XFM deposits are deposited on several structures in the anterior segment of the eye including the lens, ciliary body, iris and trabecular meshwork in XFG.…”