Molecular complexity of primary open angle glaucoma: current concepts

Abstract

Glaucoma is a group of heterogeneous optic neuropathies with complex genetic basis. Among the three principle subtypes of glaucoma, primary open angle glaucoma (POAG) occurs most frequently. Till date, 25 loci have been found to be linked to POAG. However, only three underlying genes (Myocilin, Optineurin and WDR36) have been identified. In addition, at least 30 other genes have been reported to be associated with POAG. Despite strong genetic influence in POAG pathogenesis, only a small part of the disease can be explained in terms of genetic aberration. Current concepts of glaucoma pathogenesis suggest it to be a neurodegenerative disorder which is triggered by different factors including mechanical stress due to intra-ocular pressure, reduced blood flow to retina, reperfusion injury, oxidative stress, glutamate excitotoxicity, and aberrant immune response. Here we present a mechanistic overview of potential pathways and crosstalk between them operating in POAG pathogenesis.

Induced Pluripotent Stem Cells Restore Function in a Human Cell Loss Model of Open-Angle Glaucoma

“…Furthermore, these drug treatments often become ineffective, forcing laser treatments or invasive surgical interventions. Although much of glaucoma is of genetic origin, it has become clear that no single genetic locus is responsible for more than a small portion of glaucoma [10][11][12][13]49]. To date, these various genetic causes of glaucoma have not converged on a single etiologic pathway.…”

“…Although the molecular etiology of glaucoma remains poorly understood, genetic and some environmental factors are important [7,[10][11][12][13]. No single gene defect is responsible for more than a small fraction of OAG cases.…”

Glaucoma Genetics – Regulation of Cell Surviving and Death in the Retina

“…These mechanisms and their potential therapeutic effects include inflammation, ischaemia, excitotoxicity, oxidative stress, mitochondrial dysfunction, and neurotrophin deprivation. Taking into consideration that apoptosis significantly contributes to ganglion cell loss in glaucoma, and in the case that the specific apoptosis signalling pathways for glaucoma can be known (Ray & Mookherjee 2009), any agent that can help to block or interrupt the specific signalling, may have the potential to slowing or stopping glaucoma progression and visual loss. Charles et al, (2005) investigated the apoptosis-related signaling pathways in a cultured rat retinal ganglion cell (RGC-5) line deprived of growth factors after serum withdrawal from the culture medium.…”

“…External and internal factors, as those within the retina and optic nerve ultrastructure, are important in the development and progression of primary open-angle glaucoma (POAG) (Lutjen-Drecoll et al, 1986;Hernandez et al, 1991;Triviño et al, 1996). More recent scientific knowledge revealed a complex situation in which other factors, as the circulatory (Yanagi et al, 2010), inflammatory (Kumarasamy et al, 2006), toxicologic (Schori et al, 2001), biochemical and molecular (Zanón-Moreno & Pinazo-Durán, 2008;Zanón-Moreno et al, 2008Ray & Mookherjee, 2009, Osborne, 2010, are likely to be involved in the pathogenesis of glaucomatous optic neuropathy. Whatever may be the real factors involved in glaucoma pathogenesis, the glaucomatous eyes suffer the dysfunction and death of the retinal ganglion cells leading to optic atrophy and irreversible visual loss.…”

Oxidative Stress in Anterior Segment of Primary Open Angle Glaucoma

“…Optineurin protects the cell from oxidative damage and blocks the release of cytochrome c from mitochondria (De Marco et al 2006). Its presence in glaucomatous AH suggests an antiapoptotic attempt by TM cells through NFk-B pathway regulation (Ray and Mookherjee 2009). Conversely, the presence of ankyrin bears witness to the TM cells degenerative process (Scotland et al 1998).…”