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Alternate Causes for Pathogenesis of Exfoliation Glaucoma
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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.

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Table of Contents

    1. Potential Role of miRNAs in Exfoliation Glaucoma (XFG)

    MicroRNAs are small, noncoding RNAs, 21–25 nucleotides in length, that regulate gene expression by binding to the 3′-untranslated region (UTR) of specific messenger RNAs (mRNAs) for degradation or translational repression [1][2][3][4][5]. The expression of miRNAs is often typical for a particular tissue or during essential cellular processes [1][2][3][4][5][6]. A single miRNA can modulate the expression of multiple mRNAs that regulate various physiological processes such as hematopoiesis, proliferation, tissue differentiation, cell-type identity maintenance, apoptosis, signal transduction, and organ development by regulating the expression of various genes [6][7][8][9]. They may exist in a stable state within cells or outside cells in biological fluids, including plasma and aqueous humor (AH), vitreous humor, serum, saliva, urine, and tears, and can exist as exosomes or be bound to carrier proteins [10][11]. Previous studies have reported that the expression of miRNAs can be involved in senescence or age-related neurological disorders, diabetes, degenerative arthritis, carcinomas, and cataracts [6][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. In glaucoma, miRNAs can regulate extracellular matrix (ECM) metabolism by regulating TGF-β and can regulate stiffness by the accelerated maturation of ECM proteins, altering the trabecular meshwork (TM) contractile properties, thus accelerating or inhibiting TM cell senescence, or by modulating oxidative- and mechanical-stress-induced damage [10][12][28] in the cell/tissue. Alterations in the miRNA levels may indicate pathogenic processes underlying disease or a stage transition of the specific disease. Thus, miRNAs serve as valuable noninvasive biomarkers for various diseases and help to prognosticate the severity of diseases that are caused by the modulation of the specific processes that they regulate [5][17].
    The role of miRNAs in glaucoma remains unclear, with several studies reporting miRNAs specifically expressed in the AH or serum in eyes with glaucoma [5][11][13][29][30]. Drewry et al. found three miRNAs (miR-125b-5p, miR-302d-3p, and miR-451a) and five miRNAs (miR-122-5p, miR-3144-3p, miR-320a, miR-320e, and miR-630) to be significantly differentially expressed in the AH of primary open-angle glaucoma (POAG) and XFG eyes, respectively, compared to controls [31]. Pathway analysis revealed that these miRNAs are involved in potential glaucoma pathways including tight junctions and TGF-β signaling, all of which are known in XFS pathogenesis. Another study, however, found no difference in miRNA expression between the different kinds of primary glaucoma, though hsa-miR-6722-3p, hsa-miR-184, and hsa-miR-1260b were more frequently found in XFG and POAG, respectively [32]. Another study identified higher levels of expression of 20 miRNAs in XFG and POAG patients than in controls, with 6 out of the 20 miRNAs (miR-637, miR-99b-3p, miR-4725-3p, miR-4724-5p, miR-4358, and miR-433-3p) elevated in both plasma and AH [33]. It was  found that 12 out of 84 miRNAs to be upregulated in XFG. Out of these 12, 3 miRNAs (hsa-miR-122-5p, hsa-miR-124-3p, and hsa-miR-424-5p) were involved in pathways, namely, TGF-β1, fibrosis/ECM, and proteoglycan metabolism with common effectors such as SMAD3/2 [34]. Phenotype comparisons with fibrosis-related miRNA gave similar results, with hsa-miR-19a-3p and hsa-miR-30a-5p related to proteoglycans being significantly downregulated in ocular hypertension (OHT) compared to XFG. Flaky aggregates are visibly seen deposited on the lenses of XFS/XFG patients. With its monolayer structure and direct exposure to ultraviolet radiation, the lens capsule epithelium is a significant subject for exploring complex elements, including genetics and environmental influences in XFS. Tomczyk-Socha et al. reported the upregulation of miR-125b in the lens capsules of XFS patients when compared to controls (cataract), with no significant upregulation in the XFG patients [35].
    It is believed that concentrating on the polymorphisms in the miRNA biogenesis pathway and their dynamic interaction with the genes under specific environmental triggers could uncover data for disease anticipation and pharmacogenomics in exfoliation syndrome (XFS) [35][36][37]. Recently, various studies have reported differential miRNA expression status in the AH and trabecular meshwork, two anatomical structures that are closely related to glaucoma, and linked them to the apoptosis of retinal ganglion cells and IOP [11][28][29]. Fewer studies, however, have reported polymorphisms in miRNA [36][37][38][39]. One study reported rs1057035 polymorphisms in the 3′-UTR of the DICER gene to be associated with a decreased risk of XFG, and rs55671916 in the 3′-UTR of the exportin 5 (XPO5) gene with an increased risk of XFG [40][38]. As per the miRNASNP database, the polymorphism rs11382316 results in a gain of function of miRNA-3161 in the genes caveolin-1 (CAV1), cytochrome P450 family 1 subfamily B member 1 (CYP1B1), and CACNA1A, and a loss of function of transforming growth factor-beta receptor 3 (TGFBR3). This result seems to further support a previously reported implication of the CACNA1A gene in XFS susceptibility [41].
    Given the significance of ECM elements to the ordinary physiology of the outpouring pathway, miRNAs that control ECM metabolism could be reasonable targets to impact AH dynamics in exfoliation syndrome (XFS) eyes. The best-described group of miRNAs that directs ECM digestion is the miR-29 family, including hsa-miR-29a, hsa-miR-29b, and hsa-miR-29c. In a study by Luna et al., the transfection of TM cells with miR-29b mimic caused the downregulation of various ECM genes, including collagens and fibronectin, as well as the targeting of genes involved in ECM remodeling (SPARC/osteonectin). Interestingly, persistent oxidative stress induced by incubation at 40% oxygen led to a critical downregulation of miR-29b in  trabecular meshwork (TM) cell lines that were related to an increased expression of several ECM genes [42]. Strategies to elevate miR-29 expression in TM cells may be advantageous to limit ECM deposition, avert cell loss, and maintain normal levels of AH outflow facility. However, this family has not been studied in targeting TM function in XFG eyes, nor has its role in XFS and XFG eyes been identified in any study. Further, the regulation of miRNA biogenesis and the TGF-β pathway in exfoliation remains unexplored. A detailed study in this direction may give insights into how TGF-β-regulated processes are modulated differentially in disease progression or in different ethnic populations.

    2. Autophagy and Mitochondrial Dysfunction and Protein Aggregate Clearance

    It was recently demonstrated a decreased UPR clearance in XFG compared to earlier forms of the disease associated with increased TGF levels in all disease stages, which suggest the potential regulation of the autophagy pathway and TGF–autophagy cross-talk involved in cell repair and aggregate clearance [43]. Autophagy is an intracellular trafficking system that conveys cytosolic constituents to the lysosome for ensuing degradation, which is crucial for misfolded protein clearance, cell homeostasis by ubiquitin–proteasomal degradation, and cell repair [44][45][46][47][48]. Immunohistochemical and mass spectrometry investigations have uncovered that exfoliative material is a profoundly glycosylated proteinaceous complex that is very impervious to degradation, both inside the body and under experimental conditions [44]. Given the significance of the autophagic clearance of protein aggregates, autophagy-related genes (ATG genes) might be involved in XFG pathology beyond primary glaucoma [46]. Studies have also shown the association of neurodegeneration with mitochondrial dysfunction and abnormal mitophagy [49][50][51]. Impaired mitophagy causes the accumulation of damaged mitochondria that may have a severe impact on acell’s ability to manage oxidative insult and/or ability to clear misfolded proteins, which may be impaired in XFG eyes. A decreased autophagic flux (an indicator of autophagic activity) caused by oxidative stress may be one of the factors that lead to the progressive failure of cellular TM function with age [52][53][54][55][56].  Autophagy genes were abruptly upregulated in severe POAG and primary angle-closure glaucoma (PACG) compared to moderate glaucoma, suggesting the role of autophagy in disease progression [46].
    In summary, research related to mitochondrial dysfunction and impaired mitophagy in XFG has been less extensive to date, with very few studies evaluating the role of the environment in triggering the dysregulation of these processes in XFG. There is a compelling need to supplement the existing literature on XFG pathogenesis with functional studies analyzing various populations and different environmental influences on mitochondrial function in XFS/XFG.

    3. The Blood–Aqueous Barrier in Eyes with Exfoliation Syndrome

    The eye, similar to the brain, is an organ endowed with immune privilege, an attribute conferred by complex ocular barrier systems. Two kinds of barriers have been distinguished inside the eye, each described by its unique tissue restriction, immunologic properties, and physiological capacities, namely, the blood–aqueous barrier (BAB) and the blood–retina barrier (BRB) [57][58]. Eyes with XFS frequently show clinical signs of impairment of the BAB [59]. The breakdown of the BAB is confirmed by an elevation in AH proteins. Mice without the LOXL1 gene, a significant genetic risk factor for XFS and XFG, displayed an increased dispersion of fluorescein at the BAB, indicating the interruption of the ciliary epithelial barrier [60]. Kuchle et al. studied the alteration in the BAB in XFS patients by the histochemical staining of endogenous albumin and reported the impairment of the BAB in XFS that was confined to the iris and, to a lesser extent, may involve the ciliary body [61]. Elevated levels of AH clusterin in XFS, POAG, and XFG cases compared to controls has been reported by several studies [62][63]. Zenkel et al. [64] reasoned that this was due to the disintegration of the BAB and leakage of systemic clusterin into the AH. On the other hand, Doudevski et al. [63] contended that this increase could not be explained by the breakdown of the BAB alone and that local synthesis might therefore play a significant role. Yildirim et al. found that serum interleukine 6 (IL-6) levels were altogether higher in XFS when contrasted with controls, suggesting higher levels of subclinical inflammation and BAB in XFS patients [65]. Kondkar et al. observed that higher plasma tumor necrosis factor alpha (TNF-α) levels might be a marker for the progression of XFS to XFG [66]. What triggers the disruption of BAB in XFS patients is unclear, though some risk factors such as oxidative stress, raised homocysteine, AH nitric oxide (NO), and vascular endothelial growth factor (VEGF) are presumed to play a role. Eraslan et al. revealed high acylated ghrelin/ghrelin proportions in XFG cases and suggested that acylated ghrelin may adversely trigger prostaglandin and NO release in XFG, causing progressive damage [67]. Bleich et al. observed that significantly elevated (twofold) homocysteine levels in the AH and the plasma of XFG patients with aqueous homocysteine was significantly correlated with corresponding plasma levels [68]. VEGF is also known to increase vascular permeability, contributing to disrupted BABs in XFS [69][70]. This may also explain the frequent ischemic systemic associations in XFS patients, including cardiovascular disease, transient ischemic attacks, and vascular occlusive disease. The mean AH and plasma VEGF concentrations and the mean AH NO concentrations were significantly higher in patients with XFG than in controls [69][70][71]. Studies have reported marginally higher mean AH and plasma levels of NO and VEGF in XFG than in patients with XFS, but the differences were not statistically significant. These studies imply a need for further studies on how these factors cause BAB breakdown and precipitate a cascade of protein complex aggregate accumulation over different ocular structures in XFS. It may be worthwhile exploring the role of ambient light and continued TGF-β exposure in the key downstream pathways such as autophagy, the disruption of the BAB, mitochondrial dysfunction, and oxidative stress in the TM cells causing functional damage. Understanding these processes in animal or invitro models would be crucial to identify mechanisms to reverse or dissolve these aggregates and prevent tissue dysfunction in XFG.


    1. Filipowicz, W.; Bhattacharyya, S.N.; Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat. Rev. Genet. 2008, 9, 102–114.
    2. Chen, K.; Rajewsky, N. The evolution of gene regulation by transcription factors and microRNAs. Nat. Rev. Genet. 2007, 8, 93–103.
    3. Bentwich, I.; Avniel, A.; Karov, Y.; Aharonov, R.; Gilad, S.; Barad, O.; Barzilai, A.; Einat, P.; Einav, U.; Meiri, E.; et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nat. Genet. 2005, 37, 766–770.
    4. Nitschke, L.; Tewari, A.; Coffin, S.L.; Xhako, E.; Pang, K.; Gennarino, V.A.; Johnson, J.L.; Blanco, F.A.; Liu, Z.; Zoghbi, H.Y. miR760 regulates ATXN1 levels via interaction with its 5′ untranslated region. Genes Dev. 2020, 34, 1147–1160.
    5. Guo, R.; Shen, W.; Su, C.; Jiang, S.; Wang, J. Relationship between the pathogenesis of glaucoma and miRNA. Ophthalmic Res. 2017, 57, 194–199.
    6. Undi, R.B.; Kandi, R.; Gutti, R.K. MicroRNAs as Haematopoiesis Regulators. Adv. Hematol. 2013, 2013, 695754.
    7. Lu, B.; Christensen, I.T.; Ma, L.W.; Wang, X.L.; Jiang, L.F.; Wang, C.X.; Feng, L.; Zhang, J.S.; Yan, Q.C. miR-24-p53 pathway evoked by oxidative stress promotes lens epithelial cell apoptosis in age-related cataracts. Mol. Med. Rep. 2018, 17, 5021–5028.
    8. Wang, Y.; Li, F.; Wang, S. MicroRNA-93 is overexpressed and induces apoptosis in glaucoma trabecular meshwork cells. Mol. Med. Rep. 2016, 14, 5746–5750.
    9. Jayaram, H.; Cepurna, W.O.; Johnson, E.C.; Morrison, J.C. MicroRNA Expression in the Glaucomatous Retina. Investig. Ophthalmol. Vis. Sci. 2015, 56, 7971–7982.
    10. Weber, J.A.; Baxter, D.H.; Zhang, S.; Huang, D.Y.; How Huang, K.; Jen, L.M.; Galas, D.J.; Wang, K. The microRNA spectrum in 12 body fluids. Clin. Chem. 2010, 56, 1733–1741.
    11. Tanaka, Y.; Tsuda, S.; Kunikata, H.; Sato, J.; Kokubun, T.; Yasuda, M.; Nishiguchi, K.M.; Inada, T.; Nakazawa, T. Profiles of extracellular miRNAs in the aqueous humor of glaucoma patients assessed with a microarray system. Sci. Rep. 2014, 4, 5089.
    12. Lee, Y.H.; Kim, S.Y.; Bae, Y.S. Upregulation of miR-760 and miR-186 is associated with replicative senescence in human lung fibroblast cells. Mol. Cells 2014, 37, 620–627.
    13. Liu, Y.; Chen, Y.; Wang, Y.; Zhang, X.; Gao, K.; Chen, S.; Zhang, X. microRNA profiling in glaucoma eyes with varying degrees of optic neuropathy by using next-generation sequencing. Investig. Ophthalmol. Vis. Sci. 2018, 59, 2955–2966.
    14. Peng, C.H.; Liu, J.H.; Woung, L.C.; Lin, T.J.; Chiou, S.H.; Tseng, P.C.; Du, W.Y.; Cheng, C.K.; Hu, C.C.; Chien, K.H.; et al. MicroRNAs and cataracts: Cor-relation among let-7 expression, age and severity of lens opacity. Br. J. Ophthalmol. 2012, 96, 747–751.
    15. Sand, M.; Gambichler, T.; Sand, D.; Skrygan, M.; Altmeyer, P.; Bechara, F.G. MicroRNAs and the skin: Tiny players in the body’s largest organ. J. Dermatol. Sci. 2009, 53, 169–175.
    16. Khee, S.G.; Yusof, Y.A.; Makpol, S. Expression of senescence-associated microRNAs and target genes in cellular aging and modulation by tocotrienol-rich fraction. Oxidative Med. Cell. Longev. 2014, 2014, 725929.
    17. Kim, J.; Yoon, H.; Chung, D.E.; Brown, J.L.; Belmonte, K.C.; Kim, J. miR-186 is decreased in aged brain and suppresses BACE 1 expression. J. Neurochem. 2016, 137, 436–445.
    18. Lou, G.; Xu, W.; Dong, F.; Chen, G.; Liu, Y. Plasma miR-17, miR-20a, miR-20b and miR-122 as potential biomarkers for diagnosis of NAFLD in type 2 diabetes mellitus patients. Life Sci. 2018, 208, 201–207.
    19. Xiu, C.; Jiang, J.; Song, R. Expression of miR-34a in cataract rats and its related mechanism. Exp. Ther. Med. 2020, 19, 1051–1057.
    20. Pan, Y.J.; Wei, L.L.; Wu, X.J.; Huo, F.C.; Mou, J.; Pei, D.S. MiR-106a-5p inhibits the cell migration and invasion of renal cell carcinoma through targeting PAK5. Cell Death Dis. 2017, 8, e3155.
    21. Que, T.; Song, Y.; Liu, Z.; Zheng, S.; Long, H.; Li, Z.; Liu, Y.; Wang, G.; Liu, Y.; Zhou, J.; et al. Decreased miRNA-637 is an unfavorable prognosis marker and promotes glioma cell growth; migration and invasion via direct targeting Akt1. Oncogene 2015, 34, 4952–4963.
    22. Shi, X.B.; Xue, L.; Yang, J.; Ma, A.H.; Zhao, J.; Xu, M.; Tepper, C.G.; Evans, C.P.; Kung, H.J.; deVere White, R.W. An androgen-regulated miRNA suppresses Bak1 expression and induces BACE1 expression. J. Neurochem. 2016, 137, 436–445.
    23. Ye, D.; Zhang, T. Androgen-independent growth of pros-tate cancer cells. Proc. Natl. Acad. Sci. USA 2007, 104, 19983–19988.
    24. Thomson, J.M.; Newman, M.; Parker, J.S.; Morin-Kensicki, E.M.; Wright, T.; Hammond, S.M. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006, 20, 2202–2207.
    25. Xu, J.; Li, J.; Zheng, T.H.; Bai, L.; Liu, Z.J. MicroRNAs in the occurrence and development of primary hepatocellular carcinoma. Adv. Clin. Exp. Med. 2016, 25, 971–975.
    26. Zhang, J.F.; He, M.L.; Fu, W.M.; Wang, H.; Chen, L.Z.; Zhu, X.; Chen, Y.; Xie, D.; Lai, P.; Chen, G.; et al. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. Hepatology 2011, 54, 2137–2148.
    27. Zhang, J.F.; Fu, W.M.; He, M.L.; Wang, H.; Wang, W.M.; Yu, S.C.; Bian, X.W.; Zhou, J.; Lin, M.C.; Lu, G.; et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol. Biol. Cell 2011, 22, 3955–3961.
    28. Youngblood, H.; Cai, J.; Drewry, M.D.; Helwa, I.; Hu, E.; Liu, S.; Yu, H.; Mu, H.; Hu, Y.; Perkumas, K.; et al. Expression of mRNAs; miRNAs; and lncRNAs in Human Trabecular Meshwork Cells Upon Mechanical Stretch. Investig. Ophthalmol. Vis. Sci. 2020, 61, 2.
    29. Jayaram, H.; Phillips, J.I.; Lozano, D.C.; Choe, T.E.; Cepurna, W.O.; Johnson, E.C.; Morrison, J.C.; Gattey, D.M.; Saugstad, J.A.; Keller, K.E. Comparison of MicroRNA expression in aqueous humor of normal and primary open-angle glaucoma patients using PCR arrays: A pilot study. Investig. Ophthalmol. Vis. Sci. 2017, 58, 2884–2890.
    30. Li, X.; Zhao, F.; Xin, M.; Li, G.; Luna, C.; Li, G.; Zhou, Q.; He, Y.; Yu, B.; Olson, E.; et al. Regulation of intraocular pressure by microRNA cluster miR-143/145. Sci. Rep. 2017, 7, 915.
    31. Drewry, M.D.; Challa, P.; Kuchtey, J.G.; Navarro, I.; Helwa, I.; Hu, Y.; Mu, H.; Stamer, W.D.; Kuchtey, R.W.; Liu, Y. Differentially expressed microRNAs in the aqueous humor of patients with exfoliation glaucoma or primary open-angle glaucoma. Hum. Mol. Genet. 2018, 27, 1263–1275.
    32. Kosior-Jarecka, E.; Czop, M.; Gasińska, K.; Wróbel-Dudzińska, D.; Zalewski, D.P.; Bogucka-Kocka, A.; Kocki, J.; Żarnowski, T. MicroRNAs in the aqueous humor of patients with different types of glaucoma. Graefe’s Arch. Clin. Exp. Ophthalmol. 2021, 259, 2337–2349.
    33. Hindle, A.G.; Thoonen, R.; Jasien, J.V.; Grange, R.M.H.; Amin, K.; Wise, J.; Ozaki, M.; Ritch, R.; Malhotra, R.; Buys, E.S. Identification of Candidate miRNA Biomarkers for Glaucoma. Investig. Ophthalmol. Vis. Sci. 2019, 60, 134–146.
    34. Rao, A.; Chakraborty, M.; Roy, A.; Sahay, P.; Pradhan, A.; Raj, N. Differential miRNA Expression: Signature for Glaucoma in Exfoliation. Clin. Ophthalmol. 2020, 14, 3025–3038.
    35. Tomczyk-Socha, M.; Baczyńska, D.; Przeździecka-Dołyk, J.; Turno-Kręcicka, A. MicroRNA-125b overexpression in exfoliation syndrome. Adv. Clin. Exp. Med. Off. Organ Wroc. Med. Univ. 2020, 29, 1399–1405.
    36. Moschos, M.M.; Dettoraki, M.; Karekla, A.; Lamprinakis, I.; Damaskos, C.; Gouliopoulos, N.; Tibilis, M.; Gazouli, M. Polymorphism analysis of miR182 and CDKN2B genes in Greek patients with primary open angle glaucoma. PLoS ONE 2020, 15, e0233692.
    37. He, J.; Zhao, J.; Zhu, W.; Qi, D.; Wang, L.; Sun, J.; Wang, B.; Ma, X.; Dai, Q.; Yu, X. MicroRNA biogenesis pathway genes polymorphisms and cancer risk: A systematic review and meta-analysis. PeerJ 2016, 4, e2706.
    38. Chatzikyriakidou, A.; Founti, P.; Melidou, A.; Minti, F.; Bouras, E.; Anastasopoulos, E.; Pappas, T.; Haidich, A.B.; Lambropoulos, A.; Topouzis, F. MicroRNA-related polymorphisms in exfoliation syndrome; pseudoexfoliative glaucoma; and primary open-angle glaucoma. Ophthalmic Genet. 2018, 39, 603–609.
    39. Saeki, M.; Watanabe, M.; Inoue, N.; Tokiyoshi, E.; Takuse, Y.; Arakawa, Y.; Hidaka, Y.; Iwatani, Y. DICER and DROSHA gene expression and polymorphisms in autoimmune thyroid diseases. Autoimmunity 2016, 49, 514–522.
    40. Jeng, S.M.; Karger, R.A.; Hodge, D.O.; Burke, J.P.; Johnson, D.H.; Good, M.S. The risk of glaucoma in exfoliation syndrome. J. Glaucoma 2007, 16, 117–121.
    41. Aung, T.; Ozaki, M.; Mizoguchi, T.; Allingham, R.R.; Li, Z.; Haripriya, A.; Nakano, S.; Uebe, S.; Harder, J.M.; Chan, A.S.; et al. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat. Genet. 2015, 47, 387–392.
    42. Luna, C.; Li, G.; Qiu, J.; Epstein, D.L.; Gonzalez, P. Role of miR-29b on the regulation of the extracellular matrix in human trabecular meshwork cells under chronic oxidative stress. Mol. Vis. 2009, 15, 2488–2497.
    43. Chakraborty, M.; Sahay, P.; Rao, A. Primary Human Trabecular Meshwork Model for Pseudoexfoliation. Cells 2021, 10, 3448.
    44. Sharma, S.; Chataway, T.; Klebe, S.; Griggs, K.; Martin, S.; Chegeni, N.; Dave, A.; Zhou, T.; Ronci, M.; Voelcker, N.H.; et al. Novel protein constituents of pathological ocular exfoliation syndrome deposits identified with mass spectrometry. Mol. Vis. 2018, 24, 801–817.
    45. Wolosin, J.M.; Ritch, R.; Bernstein, A.M. Is Autophagy Dysfunction a Key to Exfoliation Glaucoma? J. Glaucoma 2018, 27, 197–201.
    46. Rao, A.; Sahay, P.; Chakraborty, M.; Prusty, B.K.; Srinivasan, S.; Jhingan, G.D.; Mishra, P.; Modak, R.; Suar, M. Switch to Autophagy the Key Mechanism for Trabecular Meshwork Death in Severe Glaucoma. Clin. Ophthalmol. 2021, 15, 3027–3039.
    47. De Juan-Marcos, L.; Escudero-Domínguez, F.A.; Hernández-Galilea, E.; Cruz-González, F.; Follana-Neira, I.; González-Sarmiento, R. Investigation of Association between Autophagy-Related Gene Polymorphisms and Exfoliation Syndrome and Exfoliation Glaucoma in a Spanish Population. Semin. Ophthalmol. 2018, 33, 361–366.
    48. Want, A.; Gillespie, S.R.; Wang, Z.; Gordon, R.; Iomini, C.; Ritch, R.; Wolosin, J.M.; Bernstein, A.M. Autophagy and Mitochondrial Dysfunction in Tenon Fibroblasts from Exfoliation Glaucoma Patients. PLoS ONE 2016, 11, e0157404.
    49. Chistiakov, D.A.; Sobenin, I.A.; Revin, V.V.; Orekhov, A.N.; Bobryshev, Y.V. Mitochondrial aging and age-related dysfunction of mitochondria. BioMed Res. Int. 2014, 2014, 238463.
    50. Manickam, A.H.; Michael, M.J.; Ramasamy, S. Mitochondrial genetics and therapeutic overview of Leber’s hereditary optic neuropathy. Indian J. Ophthalmol. 2017, 65, 1087–1092.
    51. Tanwar, M.; Dada, T.; Sihota, R.; Dada, R. Mitochondrial DNA analysis in primary congenital glaucoma. Mol. Vis. 2010, 16, 518–533.
    52. Izzotti, A.; Longobardi, M.; Cartiglia, C.; Sacca, S.C. Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. PLoS ONE 2011, 6, e14567.
    53. Porter, K.; Nallathambi, J.; Lin, Y.; Liton, P.B. Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells: Implications for glaucoma pathogenesis. Autophagy 2013, 9, 581–594.
    54. Liton, P.B.; Lin, Y.; Gonzalez, P.; Epstein, D.L. Potential role of lysosomal dysfunction in the pathogenesis of primary open angle glaucoma. Autophagy 2009, 5, 122–124.
    55. Abu-Amero, K.K.; Morales, J.; Bosley, T.M. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Investig. Ophthalmol. Vis. Sci. 2006, 47, 2533–2541.
    56. Sundaresan, P.; Simpson, D.A.; Sambare, C.; Duffy, S.; Lechner, J.; Dastane, A.; Dervan, E.W.; Vallabh, N.; Chelerkar, V.; Deshpande, M.; et al. Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants. Genet. Med. Off. J. Am. Coll. Med. Genet. 2015, 17, 279–284.
    57. Coca-Prados, M. The blood-aqueous barrier in health and disease. J. Glaucoma 2014, 23, S36–S38.
    58. Bill, A. The blood-aqueous barrier. Trans. Ophthalmol. Soc. UK 1986, 105, 149–155.
    59. Küchle, M.; Vinores, S.A.; Mahlow, J.; Green, W.R. Blood-aqueous barrier in exfoliation syndrome: Evaluation by immunohistochemical staining of endogenous albumin. Graefe’s Arch. Clin. Exp. Ophthalmol. 1996, 234, 12–18.
    60. Wiggs, J.L.; Pawlyk, B.; Connolly, E.; Adamian, M.; Miller, J.W.; Pasquale, L.R.; Haddadin, R.I.; Grosskreutz, C.L.; Rhee, D.J.; Li, T. Disruption of the blood-aqueous barrier and lens abnormalities in mice lacking lysyl oxidase-like 1 (LOXL1). Investig. Ophthalmol. Vis. Sci. 2014, 55, 856–864.
    61. Küchle, M.; Nguyen, N.X.; Hannappel, E.; Naumann, G.O. The blood-aqueous barrier in eyes with exfoliation syndrome. Ophthalmic Res. 1995, 27, 136–142.
    62. Yavrum, F.; Elgin, U.; Kocer, Z.A.; Fidanci, V.; Sen, E. Evaluation of aqueous humor and serum clusterin levels in patients with glaucoma. BMC Ophthalmol. 2021, 21, 25.
    63. Doudevski, I.; Rostagno, A.; Cowman, M.; Liebmann, J.; Ritch, R.; Ghiso, J. Clusterin and complement activation in exfoliation glaucoma. Investig. Ophthalmol. Vis. Sci. 2014, 55, 2491–2499.
    64. Zenkel, M.; Kruse, F.E.; Jünemann, A.G.; Naumann, G.O.; Schlötzer-Schrehardt, U. Clusterin deficiency in eyes with exfoliation syndrome may be implicated in the aggregation and deposition of pseudoexfoliative material. Investig. Ophthalmol. Vis. Sci. 2006, 47, 1982–1990.
    65. Yildirim, Z.; Yildirim, F.; Uçgun, N.I.; Sepici-Dinçel, A. The role of the cytokines in the pathogenesis of exfoliation syndrome. Int. J. Ophthalmol. 2013, 6, 50–53.
    66. Kondkar, A.; Azad, T.A.; Almobarak, F.; Kalantan, H.; Al-Obeidan, S.A.; Abu-Amero, K.K. Elevated levels of plasma tumor necrosis factor alpha in patients with exfoliation glaucoma. Clin. Ophthalmol. 2018, 12, 153–159.
    67. Eraslan, N.; Elgin, U.; Şen, E.; Kilic, A.; Yilmazbas, P. Comparison of total/active ghrelin levels in primary open angle glaucoma; exfoliation glaucoma and exfoliation syndrome. Int. J. Ophthalmol. 2018, 11, 823–827.
    68. Bleich, S.; Roedl, J.; Von Ahsen, N.; Schlötzer-Schrehardt, U.; Reulbach, U.; Beck, G.; Kruse, F.E.; Naumann, G.O.; Kornhuber, J.; Jünemann, A.G. Elevated homocysteine levels in aqueous humor of patients with exfoliation glaucoma. Am. J. Ophthalmol. 2004, 138, 162–164.
    69. Kuroki, M.; Voest, E.E.; Amano, S.; Beerepoot, L.V.; Takashima, S.; Tolentino, M.; Kim, R.Y.; Rohan, R.M.; Colby, K.A.; Yeo, K.T.; et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J. Clin. Investig. 1996, 98, 1667–1675.
    70. Borazan, M.; Karalezli, A.; Kucukerdonmez, C.; Bayraktar, N.; Kulaksizoglu, S.; Akman, A.; Akova, Y.A. Aqueous humor and plasma levels of vascular endothelial growth factor and nitric oxide in patients with exfoliation syndrome and exfoliation glaucoma. J. Glaucoma 2010, 19, 207–211.
    71. Aiello, L.P.; Northrup, J.M.; Keyt, B.A.; Takagi, H.; Iwamoto, M.A. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch. Ophthalmol. 1995, 113, 1538–1544.
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      Chakraborty, M. Alternate Causes for Pathogenesis of Exfoliation Glaucoma. Encyclopedia. Available online: (accessed on 02 February 2023).
      Chakraborty M. Alternate Causes for Pathogenesis of Exfoliation Glaucoma. Encyclopedia. Available at: Accessed February 02, 2023.
      Chakraborty, Munmun. "Alternate Causes for Pathogenesis of Exfoliation Glaucoma," Encyclopedia, (accessed February 02, 2023).
      Chakraborty, M. (2022, March 11). Alternate Causes for Pathogenesis of Exfoliation Glaucoma. In Encyclopedia.
      Chakraborty, Munmun. ''Alternate Causes for Pathogenesis of Exfoliation Glaucoma.'' Encyclopedia. Web. 11 March, 2022.