Salient Genetic and Proteomic Pathways in Glaucoma

Glaucoma, the second leading cause of blindness worldwide is a neurodegenerative disease, with or without elevated ocular pressure, exhibiting several different phenotypic presentations, which result in progressive visual field loss after compromise of retinal ganglion cells and their axons to the optic nerve and brain. Predominant clinical glaucoma types are primary open angle, POAG, angle closure, and congenital; secondary glaucomas are: psuedoexfoliaiton, pigmentary, neovascular, traumatic, iridoendothelial, and uveitic glaucoma. In each of these types of glaucoma, genetic, epigenetic, proteomic, environmental, and mechanical forces may converge as well to cause or advance the disease. Alternatively, but not necessarily in an independent fashion, stress related pathways of oxidative stress, inflammation, infection, trauma, immune reaction, neuro-degeneration and mutant genomic products can produce deleterious misfolded proteins, antibodies, and aggregate deposits in the trabecular meshwork, TM, raise the intraocular pressure and result in optic nerve damage and loss of vision. Examining the interplay of these stress pathways with genetic, epigenetic, proteomic, environmental and mechanical forces to gain some understanding of molecular causes of glaucoma is the goal of this paper

Keywords: Glaucoma GWAS, Myocilin mutants/misfolded proteins, Oxidative stress, HSP, Inflammation, Immune/autoimmune response, Mitochondrial lysosome axis dysfunction, Autophagy pathways, Trabecular meshwork ECM dynamics, RGC/brain neuroprotection, Epigenetic role

Abbreviations: AH: Aqueous Humor; ATP: Adenosine Triphosphate; Bcl-2: B cell lymphoma 2; CHOP: A multifunctional transcription factor in endoplasmic reticulum oxidative stress and protein misfolding; CLAN: Cross linked actin network; DARC: Detecting apoptosing retinal ganglion cell technique; ECM: Extracellular matrix; ELAM: Endothelial leukocyte cell adhesion molecule; EM: Electron microscopy; ER: Endoplasmic reticulum; GWAS: Genome wide association study; HSP: Heat shock protein; IOP: Intraocular pressure; JCT: Juxtacanalicular region of the trabecular meshwork; JNK: Jun N-Terminal Kinase; MAGP-1: Microfibril associated glycoprotein; MAP: Kinase mitogen activated protein kinase, increase ECM production in TM cells; ERK: Kinase extracellular; MAP: Microtubular kinase; MIP: Macrophage inflammatory protein; MITF: Microphthalmia associated transcription factor; MMP: Matrix metalloproteinase; MTORC-1: Mechanistic target of rapamycin complex overseas protein synthesis for Lysosome function; Myoc-OLF: Myocilin olfactomedin domain five-bladed β-propeller protein family; NAD: Nicotinamide adenine dinucleotide; NFKB: Nuclear factor kappa-light-chain-enhancer of activated B cells, major transcription factor for inflammation/immune modification in the cell; NMDA: N-methyl D Aspartate; NTG: Normal tension glaucoma; Nrf2: Nuclear factor erythroid 2, major oxidative stress transcription factor; PDS: Pigmentary dispersion syndrome; PERG: Pattern electroretinogram; PG: Pigmentary glaucoma; PI-3: Kinase phosphoinositide-3 kinase; PMEL: Premelanosome protein that may form physiologic amyloid beta protein in melanosomes; POAG: Primary open angle glaucoma; PTEN: Phosphatase and tension homologue; PTP: Mitochondrial permeability transition pore; PXG: Pseudoexfoliaiton glaucoma; PXS: Pseudoexfoliaiton syndrome; REST: Repression element silencing transcription factor; Retinal Ganglion Cell; Rho Kinase protein kinase modifying cell shape, size and adhesion; SC: Schlemm’s Canal; SPARC: Secreted Protein Acidic Rich in cysteine, binds to ECM proteins and regulate matrix metalloproteinase expression; SMAD: ‘Small Mothers against decapentaplegic homolog’ literally but actually transcription factor which mediates TGF beta transduction or simply helps transfer cytoplasmic signals to nucleus to activate molecules like MAP or Rho kinase; TEK: Receptor tyrosine kinase; TGF: Beta transforming growth factor beta (signalling differentiation, proliferation, chemotaxis and fibrosis); TIMP 3: Tissue inhibitor of metalloproteinase; TLR4: Toll like receptor 4; TM: Trabecular meshwork; TNF: Tumour necrosis factor; TNFR: Tumour necrosis factor receptor; UPR: Unfolded protein response; VCAM1: Vascular adhesion protein; VEP: Visual evoked potential