Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2017 (2017), Article ID 5712341, 12 pages
https://doi.org/10.1155/2017/5712341
Review Article

Epigenetics and Signaling Pathways in Glaucoma

Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, CT 06510, USA

Correspondence should be addressed to Ji Liu

Received 14 October 2016; Revised 28 November 2016; Accepted 13 December 2016; Published 22 January 2017

Academic Editor: Dongsheng Yan

Copyright © 2017 Angela C. Gauthier and Ji Liu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Y.-C. Tham, X. Li, T. Y. Wong, H. A. Quigley, T. Aung, and C.-Y. Cheng, “Global prevalence of glaucoma and projections of glaucoma burden through 2040. A systematic review and meta-analysis,” Ophthalmology, vol. 121, no. 11, pp. 2081–2090, 2014. View at Publisher · View at Google Scholar
  2. A. C. Gauthier and J. Liu, “Neurodegeneration and neuroprotection in glaucoma,” Yale Journal of Biology and Medicine, vol. 89, no. 1, pp. 73–79, 2016. View at Google Scholar
  3. J. L. Wiggs, “The cell and molecular biology of complex forms of glaucoma: updates on genetic, environmental, and epigenetic risk factors,” Investigative Ophthalmology & Visual Science, vol. 53, no. 5, pp. 2467–2469, 2012. View at Publisher · View at Google Scholar · View at Scopus
  4. R. C. W. Wolfs, C. C. W. Klaver, R. S. Ramrattan, C. M. Van Duijn, A. Hofman, and P. T. V. M. De Jong, “Genetic risk of primary open-angle glaucoma: population-based familial aggregation study,” Archives of Ophthalmology, vol. 116, no. 12, pp. 1640–1645, 1998. View at Publisher · View at Google Scholar · View at Scopus
  5. X. Wang, J. Harmon, N. Zabrieskie et al., “Using the Utah Population Database to assess familial risk of primary open angle glaucoma,” Vision Research, vol. 50, no. 23, pp. 2391–2395, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. S. S. Verma, J. N. Cooke Bailey, A. Lucas et al., “Epistatic gene-based interaction analyses for glaucoma in eMERGE and NEIGHBOR consortium,” PLOS Genetics, vol. 12, no. 9, Article ID e1006186, 2016. View at Publisher · View at Google Scholar
  7. J. L. Wiggs, “Genetic etiologies of glaucoma,” Archives of Ophthalmology, vol. 125, no. 1, pp. 30–37, 2007. View at Publisher · View at Google Scholar
  8. L. R. Pasquale and J. H. Kang, “Lifestyle, nutrition, and glaucoma,” Journal of Glaucoma, vol. 18, no. 6, pp. 423–428, 2009. View at Publisher · View at Google Scholar
  9. F. Ko, M. V. Boland, P. Gupta et al., “Diabetes, triglyceride levels, and other risk factors for glaucoma in the national health and nutrition examination survey 2005–2008,” Investigative Opthalmology & Visual Science, vol. 57, no. 4, pp. 2152–2157, 2016. View at Publisher · View at Google Scholar
  10. L. Xu, H. Wang, Y. Wang, and J. B. Jonas, “Intraocular pressure correlated with arterial blood pressure: The Beijing Eye Study,” American Journal of Ophthalmology, vol. 144, no. 3, pp. 461–462, 2007. View at Publisher · View at Google Scholar
  11. D. Zhao, J. Cho, M. H. Kim, and E. Guallar, “The association of blood pressure and primary open-angle glaucoma: a meta-analysis,” American Journal of Ophthalmology, vol. 158, no. 3, pp. 615.e9–627.e9, 2014. View at Publisher · View at Google Scholar
  12. M. E. Charlson, C. G. de Moraes, A. Link et al., “Nocturnal systemic hypotension increases the risk of glaucoma progression,” Ophthalmology, vol. 121, no. 10, pp. 2004–2012, 2014. View at Publisher · View at Google Scholar
  13. L. R. Pasquale, J. H. Kang, J. E. Manson, W. C. Willett, B. A. Rosner, and S. E. Hankinson, “Prospective study of type 2 diabetes mellitus and risk of primary open-angle glaucoma in women,” Ophthalmology, vol. 113, no. 7, pp. 1081–1086, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. C. A. Girkin, G. McGwin Jr., S. F. McNeal, P. P. Lee, and C. Owsley, “Hypothyroidism and the development of open-angle glaucoma in a male population,” Ophthalmology, vol. 111, no. 9, pp. 1649–1652, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. C. Lin, C. Hu, J. Ho, H. Chiu, and H. Lin, “Obstructive Sleep Apnea and Increased Risk of Glaucoma,” Ophthalmology, vol. 120, no. 8, pp. 1559–1564, 2013. View at Publisher · View at Google Scholar
  16. D. Zhao, J. Cho, M. H. Kim, D. S. Friedman, and E. Guallar, “Diabetes, fasting glucose, and the risk of glaucoma: a meta-analysis,” Ophthalmology, vol. 122, no. 1, pp. 72–78, 2015. View at Publisher · View at Google Scholar
  17. W. R. Coward, K. Watts, C. A. Feghali-Bostwick, A. Knox, and L. Pang, “Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis,” Molecular and Cellular Biology, vol. 29, no. 15, pp. 4325–4339, 2009. View at Publisher · View at Google Scholar
  18. T. Hardy and D. A. Mann, “Epigenetics in liver disease: from biology to therapeutics,” Gut, vol. 65, no. 11, pp. 1895–1905, 2016. View at Publisher · View at Google Scholar
  19. G. Tezel and M. B. Wax, “Hypoxia-inducible factor 1α in the glaucomatous retina and opticnerve head,” Archives of Ophthalmology, vol. 122, no. 9, pp. 1348–1356, 2004. View at Publisher · View at Google Scholar
  20. J. A. Watson, C. J. Watson, A.-M. McCrohan et al., “Generation of an epigenetic signature by chronic hypoxia in prostate cells,” Human Molecular Genetics, vol. 18, no. 19, pp. 3594–3604, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. K. Pennington and M. DeAngelis, “Epigenetic mechanisms of the aging human retina,” Journal of Experimental Neuroscience, vol. 92, supplement 2, pp. 51–79, 2015. View at Publisher · View at Google Scholar
  22. F. McDonnell, C. O’Brien, and D. Wallace, “The role of epigenetics in the fibrotic processes associated with glaucoma,” Journal of Ophthalmology, vol. 2014, Article ID 750459, 13 pages, 2014. View at Publisher · View at Google Scholar
  23. K. Kimura, M. Iwano, D. F. Higgins et al., “Stable expression of HIF-1α in tubular epithelial cells promotes interstitial fibrosis,” American Journal of Physiology—Renal Physiology, vol. 295, no. 4, pp. F1023–F1029, 2008. View at Publisher · View at Google Scholar
  24. R. C. Rao, A. K. Hennig, M. T. Malik, D. F. Chen, and S. Chen, “Epigenetic regulation of retinal development and disease,” Journal of Ocular Biology, Diseases, and Informatics, vol. 4, no. 3, pp. 121–136, 2011. View at Publisher · View at Google Scholar
  25. H. R. Pelzel, C. L. Schlamp, and R. W. Nickells, “Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis,” BMC Neuroscience, vol. 11, no. 1, 2010. View at Publisher · View at Google Scholar
  26. S. He, X. Li, N. Chan, and D. R. Hinton, “Review: epigenetic mechanisms in ocular disease,” Molecular Vision, vol. 19, pp. 665–674, 2013. View at Google Scholar
  27. B. R. Schwechter, L. E. Millet, and L. A. Levin, “Histone deacetylase inhibition-mediated differentiation of RGC-5 cells and interaction with survival,” Investigative Ophthalmology & Visual Science, vol. 48, no. 6, pp. 2845–2857, 2007. View at Publisher · View at Google Scholar
  28. X. Guo, A. Kimura, Y. Azuchi et al., “Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma,” Scientific Reports, vol. 6, Article ID 33950, 2016. View at Publisher · View at Google Scholar
  29. F. S. McDonnell, S. A. McNally, A. F. Clark, C. J. O'Brien, and D. M. Wallace, “Increased global DNA methylation and decreased TGFβ1 promoter methylation in glaucomatous lamina cribrosa cells,” Journal of Glaucoma, vol. 25, no. 10, pp. e834–e842, 2016. View at Publisher · View at Google Scholar · View at Scopus
  30. W. Bechtel, S. McGoohan, E. M. Zeisberg et al., “Methylation determines fibroblast activation and fibrogenesis in the kidney,” Nature Medicine, vol. 16, no. 5, pp. 544–550, 2010. View at Publisher · View at Google Scholar
  31. A. Jünemann, B. Lenz, U. Reulbach et al., “Genomic (epigenetic) DNA methylation in patients with open-angle glaucoma,” Acta Ophthalmologica, vol. 87, no. s244, 2009. View at Publisher · View at Google Scholar
  32. M. Molasy, A. Walczak, J. Szaflik, J. P. Szaflik, and I. Majsterek, “MicroRNAs in glaucoma and neurodegenerative diseases,” Journal of Human Genetics, 2016. View at Publisher · View at Google Scholar
  33. A. Izzotti, C. Ceccaroli, M. G. Longobardi et al., “Molecular damage in glaucoma: from anterior to posterior eye segment. The MicroRNA role,” MicroRNA, vol. 4, no. 1, pp. 3–17, 2015. View at Google Scholar · View at Scopus
  34. H. Jayaram, W. O. Cepurna, E. C. Johnson, and J. C. Morrison, “MicroRNA expression in the glaucomatous retina,” Investigative Opthalmology & Visual Science, vol. 56, no. 13, pp. 7971–7982, 2015. View at Publisher · View at Google Scholar
  35. W. Shen, Y. Han, B. Huang et al., “MicroRNA-483-3p inhibits extracellular matrix production by targeting smad4 in human trabecular meshwork cells,” Investigative Opthalmology & Visual Science, vol. 56, no. 13, pp. 8419–8427, 2015. View at Publisher · View at Google Scholar
  36. Y. Tanaka, S. Tsuda, H. Kunikata et al., “Profiles of extracellular miRNAs in the aqueous humor of glaucoma patients assessed with a microarray system,” Scientific Reports, vol. 4, article no. 5089, 2014. View at Publisher · View at Google Scholar
  37. G. Villarreal, D. Oh, M. H. Kang, and D. J. Rhee, “Coordinated regulation of extracellular matrix synthesis by the microRNA-29 Family in the trabecular meshwork,” Investigative Opthalmology & Visual Science, vol. 52, no. 6, pp. 3391–3397, 2011. View at Publisher · View at Google Scholar
  38. S. H. Paylakhi, H. Moazzeni, S. Yazdani et al., “FOXC1 in human trabecular meshwork cells is involved in regulatory pathway that includes miR-204, MEIS2, and ITGβ1,” Experimental Eye Research, vol. 111, pp. 112–121, 2013. View at Publisher · View at Google Scholar · View at Scopus
  39. N. Kong, X. Lu, and B. Li, “Downregulation of microRNA-100 protects apoptosis and promotes neuronal growth in retinal ganglion cells,” BMC Molecular Biology, vol. 15, no. 1, 2014. View at Publisher · View at Google Scholar
  40. B. S. Clark and S. Blackshaw, “Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease,” Frontiers in Genetics, vol. 5, article no. 164, 2014. View at Publisher · View at Google Scholar
  41. F. Li, X. Wen, H. Zhang, and X. Fan, “Novel insights into the role of long noncoding RNA in ocular diseases,” International Journal of Molecular Sciences, vol. 17, no. 4, article 478, 2016. View at Publisher · View at Google Scholar
  42. A. Congrains, K. Kamide, M. Ohishi, and H. Rakugi, “ANRIL: molecular mechanisms and implications in human health,” International Journal of Molecular Sciences, vol. 14, no. 1, pp. 1278–1292, 2013. View at Publisher · View at Google Scholar
  43. L. R. Pasquale, S. J. Loomis, J. H. Kang et al., “CDKN2B-AS1 genotype–glaucoma feature correlations in primary open-angle glaucoma patients from the United States,” American Journal of Ophthalmology, vol. 155, no. 2, pp. 342.e5–353.e5, 2013. View at Publisher · View at Google Scholar
  44. K. P. Burdon, S. MacGregor, A. W. Hewitt et al., “Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1,” Nature Genetics, vol. 43, no. 6, pp. 574–578, 2011. View at Publisher · View at Google Scholar · View at Scopus
  45. W. D. Ramdas, L. M. van Koolwijk, H. G. Lemij et al., “Common genetic variants associated with open-angle glaucoma,” Human Molecular Genetics, vol. 20, no. 12, pp. 2464–2471, 2011. View at Publisher · View at Google Scholar
  46. C. L. Pervan, “Smad-independent TGF-β2 signaling pathways in human trabecular meshwork cells,” Experimental Eye Research, 2016. View at Publisher · View at Google Scholar
  47. M. Inatani, H. Tanihara, H. Katsuta, M. Honjo, N. Kido, and Y. Honda, “Transforming growth factor-β2 levels in aqueous humor of glaucomatous eyes,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 239, no. 2, pp. 109–113, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. A. A. Ozcan, N. Ozdemir, and A. Canataroglu, “The aqueous levels of TGF-β2 in patients with glaucoma,” International Ophthalmology, vol. 25, no. 1, pp. 19–22, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. D. L. Fleenor, A. R. Shepard, P. E. Hellberg, N. Jacobson, I. Pang, and A. F. Clark, “TGFβ2-induced changes in human trabecular meshwork: implications for intraocular pressure,” Investigative Opthalmology & Visual Science, vol. 47, no. 1, pp. 226–234, 2006. View at Publisher · View at Google Scholar
  50. J. Gottanka, D. Chan, M. Eichhorn, E. Lutjen-Drecoll, and C. R. Ethier, “Effects of TGF-β2 in perfused human eyes,” Investigative Ophthalmology & Visual Science, vol. 45, no. 1, pp. 153–158, 2004. View at Google Scholar
  51. Y. Mu, S. K. Gudey, and M. Landström, “Non-Smad signaling pathways,” Cell and Tissue Research, vol. 347, no. 1, pp. 11–20, 2012. View at Publisher · View at Google Scholar
  52. C. M. McDowell, H. E. Tebow, R. J. Wordinger, and A. F. Clark, “Smad3 is necessary for transforming growth factor-beta2 induced ocular hypertension in mice,” Experimental Eye Research, vol. 116, pp. 419–423, 2013. View at Publisher · View at Google Scholar
  53. Y. E. Zhang, “Non-Smad pathways in TGF-β signaling,” Cell Research, vol. 19, no. 1, pp. 128–139, 2009. View at Publisher · View at Google Scholar
  54. H. Han, T. Wecker, F. Grehn, and G. Schlunck, “Elasticity-dependent modulation of TGF-β responses in human trabecular meshwork cells,” Investigative Opthalmology & Visual Science, vol. 52, no. 6, pp. 2889–2896, 2011. View at Publisher · View at Google Scholar
  55. P. B. Liton, G. Li, C. Luna, P. Gonzalez, and D. L. Epstein, “Cross-talk between TGF-β1 and IL-6 in human trabecular meshwork cells,” Molecular Vision, vol. 15, pp. 326–334, 2009. View at Google Scholar
  56. M. H. Kang, D. Oh, J. Kang, and D. J. Rhee, “Regulation of SPARC by transforming growth factor β2 in human trabecular meshwork,” Investigative Opthalmology & Visual Science, vol. 54, no. 4, pp. 2523–2532, 2013. View at Publisher · View at Google Scholar
  57. A. D. Bradshaw and E. H. Sage, “SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury,” Journal of Clinical Investigation, vol. 107, no. 9, pp. 1049–1054, 2001. View at Publisher · View at Google Scholar
  58. M. Yamashita, K. Fatyol, C. Jin, X. Wang, Z. Liu, and Y. E. Zhang, “TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β,” Molecular Cell, vol. 31, no. 6, pp. 918–924, 2008. View at Publisher · View at Google Scholar
  59. A. Sorrentino, N. Thakur, S. Grimsby et al., “The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner,” Nature Cell Biology, vol. 10, no. 10, pp. 1199–1207, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. M. S. Filla, M. K. Schwinn, N. Sheibani, P. L. Kaufman, and D. M. Peters, “Regulation of cross-linked actin network (CLAN) formation in human trabecular meshwork (HTM) cells by convergence of distinct β1 and β3 integrin pathways,” Investigative Opthalmology & Visual Science, vol. 50, no. 12, pp. 5723–5731, 2009. View at Publisher · View at Google Scholar
  61. A. F. Clark, D. Brotchie, A. T. Read et al., “Dexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissue,” Cell Motility and the Cytoskeleton, vol. 60, no. 2, pp. 83–95, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. P. P. Pattabiraman and P. V. Rao, “Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells,” AJP: Cell Physiology, vol. 298, no. 3, pp. C749–C763, 2010. View at Publisher · View at Google Scholar
  63. E. Papadimitriou, D. Kardassis, A. Moustakas, and C. Stournaras, “TGFβ-induced early activation of the small GTPase RhoA is smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2,” Cellular Physiology and Biochemistry, vol. 28, no. 2, pp. 229–238, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. P. V. Rao, P. P. Pattabiraman, and C. Kopczynski, “Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: bench to bedside research,” Experimental Eye Research, 2016. View at Publisher · View at Google Scholar
  65. T. Inoue and H. Tanihara, “Rho-associated kinase inhibitors: a novel glaucoma therapy,” Progress in Retinal and Eye Research, vol. 37, pp. 1–12, 2013. View at Publisher · View at Google Scholar
  66. G. Prasanna, B. Li, M. Mogi, and D. S. Rice, “Pharmacology of novel intraocular pressure-lowering targets that enhance conventional outflow facility: pitfalls, promises and what lies ahead?” European Journal of Pharmacology, vol. 787, pp. 47–56, 2016. View at Publisher · View at Google Scholar · View at Scopus
  67. M. Honjo, H. Tanihara, M. Inatani et al., “Effects of Rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility,” Investigative Ophthalmology and Visual Science, vol. 42, no. 1, pp. 137–144, 2001. View at Google Scholar · View at Scopus
  68. J. M. Sturdivant, S. M. Royalty, C. Lin et al., “Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma,” Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 10, pp. 2475–2480, 2016. View at Publisher · View at Google Scholar
  69. K. P. Garnock-Jones, “Ripasudil: first global approval,” Drugs, vol. 74, no. 18, pp. 2211–2215, 2014. View at Publisher · View at Google Scholar
  70. J. E. Johnson, Y.-A. Barde, M. Schwab, and H. Thoenen, “Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells,” Journal of Neuroscience, vol. 6, no. 10, pp. 3031–3038, 1986. View at Google Scholar · View at Scopus
  71. H. Levkovitch-Verbin, “Retinal ganglion cell apoptotic pathway in glaucoma: initiating and downstream mechanisms,” Progress in Brain Research, vol. 220, pp. 37–57, 2015. View at Publisher · View at Google Scholar · View at Scopus
  72. D. R. Anderson and A. Hendrickson, “Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve,” Investigative Ophthalmology, vol. 13, no. 10, pp. 771–783, 1974. View at Google Scholar · View at Scopus
  73. M. Almasieh, A. M. Wilson, B. Morquette, J. L. Cueva Vargas, and A. Di Polo, “The molecular basis of retinal ganglion cell death in glaucoma,” Progress in Retinal and Eye Research, vol. 31, no. 2, pp. 152–181, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Yuan and B. A. Yankner, “Apoptosis in the nervous system,” Nature, vol. 407, no. 6805, pp. 802–809, 2000. View at Publisher · View at Google Scholar
  75. H. Gao, X. Qiao, F. Hefti, J. G. Hollyfield, and B. Knusel, “Elevated mRNA expression of brain-derived neurotrophic factor in retinal ganglion cell layer after optic nerve injury,” Investigative Ophthalmology and Visual Science, vol. 38, no. 9, pp. 1840–1847, 1997. View at Google Scholar · View at Scopus
  76. A. Di Polo, L. J. Aigner, R. J. Dunn, G. M. Bray, and A. J. Aguayo, “Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells,” Proceedings of the National Academy of Sciences, vol. 95, no. 7, pp. 3978–3983, 1998. View at Publisher · View at Google Scholar
  77. N. Nafissi and M. Foldvari, “Neuroprotective therapies in glaucoma: I. Neurotrophic factor delivery,” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, vol. 8, no. 2, pp. 240–254, 2016. View at Publisher · View at Google Scholar
  78. Y. Liu, Z. Gong, L. Liu, and H. Sun, “Combined effect of olfactory ensheathing cell (OEC) transplantation and glial cell line-derived neurotrophic factor (GDNF) intravitreal injection on optic nerve injury in rats,” Molecular Vision, vol. 16, pp. 2903–2910, 2010. View at Google Scholar · View at Scopus
  79. A. Eilers, J. Whitfield, B. Shah, C. Spadoni, H. Desmond, and J. Ham, “Direct inhibition of c-Jun N-terminal kinase in sympathetic neurones prevents c-jun promoter activation and NGF withdrawal-induced death,” Journal of Neurochemistry, vol. 76, no. 5, pp. 1439–1454, 2001. View at Publisher · View at Google Scholar · View at Scopus
  80. J. Ham, A. Eilers, J. Whitfield, S. J. Neame, and B. Shah, “c-Jun and the transcriptional control of neuronal apoptosis,” Biochemical Pharmacology, vol. 60, no. 8, pp. 1015–1021, 2000. View at Publisher · View at Google Scholar · View at Scopus
  81. H. Levkovitch-Verbin, H. A. Quigley, K. R. G. Martin et al., “The transcription factor c-jun is activated in retinal ganglion cells in experimental rat glaucoma,” Experimental Eye Research, vol. 80, no. 5, pp. 663–670, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Isenmann and M. Bähr, “Expression of c-Jun protein in degenerating retinal ganglion cells after optic nerve lesion in the rat,” Experimental Neurology, vol. 147, no. 1, pp. 28–36, 1997. View at Publisher · View at Google Scholar
  83. M. Takeda, H. Kato, A. Takamiya, A. Yoshida, and H. Kiyama, “Injury-specific expression of activating transcription factor-3 in retinal ganglion cells and its colocalized expression with phosphorylated c-Jun,” Investigative Ophthalmology and Visual Science, vol. 41, no. 9, pp. 2412–2421, 2000. View at Google Scholar · View at Scopus
  84. G. Tezel, B. C. Chauhan, R. P. LeBlanc, and M. B. Wax, “Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma,” Investigative Ophthalmology and Visual Science, vol. 44, no. 7, pp. 3025–3033, 2003. View at Publisher · View at Google Scholar · View at Scopus
  85. E. C. Johnson, Y. Guo, W. O. Cepurna, and J. C. Morrison, “Neurotrophin roles in retinal ganglion cell survival: lessons from rat glaucoma models,” Experimental Eye Research, vol. 88, no. 4, pp. 808–815, 2009. View at Publisher · View at Google Scholar
  86. H. Sun, Y. Wang, IH. Pang et al., “Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension,” Molecular Vision, vol. 17, pp. 864–875, 2011. View at Google Scholar
  87. G. Tezel, X. Yang, J. Yang, and M. B. Wax, “Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice,” Brain Research, vol. 996, no. 2, pp. 202–212, 2004. View at Publisher · View at Google Scholar · View at Scopus
  88. H. Dudek, S. R. Datta, T. F. Franke et al., “Regulation of neuronal survival by the serine-threonine protein kinase Akt,” Science, vol. 275, no. 5300, pp. 661–665, 1997. View at Publisher · View at Google Scholar · View at Scopus
  89. S. R. Datta, H. Dudek, X. Tao et al., “Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery,” Cell, vol. 91, no. 2, pp. 231–241, 1997. View at Publisher · View at Google Scholar · View at Scopus
  90. H. Zhou, X. Li, J. Meinkoth, and R. N. Pittman, “Akt regulates cell survival and apoptosis at a postmitochondrial level,” The Journal of Cell Biology, vol. 151, no. 3, pp. 483–494, 2000. View at Publisher · View at Google Scholar
  91. M. K. Barthwal, “Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival,” Journal of Biological Chemistry, vol. 278, no. 6, pp. 3897–3902, 2003. View at Publisher · View at Google Scholar
  92. H. Levkovitch-Verbin, N. Harizman, R. Dardik, Y. Nisgav, S. Vander, and S. Melamed, “Regulation of cell death and survival pathways in experimental glaucoma,” Experimental Eye Research, vol. 85, no. 2, pp. 250–258, 2007. View at Publisher · View at Google Scholar · View at Scopus
  93. H. S. Kim and C. K. Park, “Retinal ganglion cell death is delayed by activation of retinal intrinsic cell survival program,” Brain Research, vol. 1057, no. 1-2, pp. 17–28, 2005. View at Publisher · View at Google Scholar · View at Scopus
  94. S. Vander and H. Levkovitch-Verbin, “Regulation of cell death and survival pathways in secondary degeneration of the optic nerve a long-term study,” Current Eye Research, vol. 37, no. 8, pp. 740–748, 2012. View at Publisher · View at Google Scholar · View at Scopus
  95. N. Takano, K. Tsuruma, Y. Ohno, M. Shimazawa, and H. Hara, “Bimatoprost protects retinal neuronal damage via Akt pathway,” European Journal of Pharmacology, vol. 702, no. 1–3, pp. 56–61, 2013. View at Publisher · View at Google Scholar · View at Scopus
  96. Y. You, V. K. Gupta, J. C. Li, N. Al-Adawy, A. Klistorner, and S. L. Graham, “FTY720 protects retinal ganglion cells in experimental glaucoma,” Investigative Opthalmology & Visual Science, vol. 55, no. 5, pp. 3060–3066, 2014. View at Publisher · View at Google Scholar
  97. R. H. Foxton, A. Finkelstein, S. Vijay et al., “VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma,” The American Journal of Pathology, vol. 182, no. 4, pp. 1379–1390, 2013. View at Publisher · View at Google Scholar
  98. R. L. Zhu, K. S. Cho, C. Y. Guo, J. Chew, D. F. Chen, and L. Yang, “Intrinsic determinants of optic nerve regeneration,” Chinese Medical Journal, vol. 126, no. 13, pp. 2543–2547, 2013. View at Google Scholar
  99. L. I. Benowitz, Z. He, and J. L. Goldberg, “Reaching the brain: advances in optic nerve regeneration,” Experimental Neurology, vol. 287, pp. 365–373, 2017. View at Publisher · View at Google Scholar
  100. Y. Koriyama, M. Kamiya, K. Arai, K. Sugitani, K. Ogai, and S. Kato, “Nipradilol promotes axon regeneration through S-nitrosylation of PTEN in retinal ganglion cells,” Advances in Experimental Medicine and Biology, vol. 801, pp. 751–757, 2014. View at Publisher · View at Google Scholar · View at Scopus
  101. K. K. Park, K. Liu, Y. Hu et al., “Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway,” Science, vol. 322, no. 5903, pp. 963–966, 2008. View at Publisher · View at Google Scholar
  102. B. J. Yungher, X. Luo, Y. Salgueiro, M. G. Blackmore, and K. K. Park, “Viral vector-based improvement of optic nerve regeneration: characterization of individual axons' growth patterns and synaptogenesis in a visual target,” Gene Therapy, vol. 22, no. 10, pp. 811–821, 2015. View at Publisher · View at Google Scholar · View at Scopus
  103. F. Sun, K. K. Park, S. Belin et al., “Sustained axon regeneration induced by co-deletion of PTEN and SOCS3,” Nature, vol. 480, no. 7377, pp. 372–375, 2011. View at Publisher · View at Google Scholar
  104. F. Bei, H. Lee, X. Liu et al., “Restoration of visual function by enhancing conduction in regenerated axons,” Cell, vol. 164, no. 1-2, pp. 219–232, 2016. View at Publisher · View at Google Scholar
  105. S. Li, Q. He, H. Wang et al., “Injured adult retinal axons with Pten and Socs3 co-deletion reform active synapses with suprachiasmatic neurons,” Neurobiology of Disease, vol. 73, pp. 366–376, 2015. View at Publisher · View at Google Scholar
  106. H. Levkovitch-Verbin, D. Makarovsky, and S. Vander, “Comparison between axonal and retinal ganglion cell gene expression in various optic nerve injuries including glaucoma,” Molecular Vision, vol. 19, pp. 2526–2541, 2013. View at Google Scholar · View at Scopus
  107. J.-C. Martinou, M. Dubois-Dauphin, J. K. Staple et al., “Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia,” Neuron, vol. 13, no. 4, pp. 1017–1030, 1994. View at Publisher · View at Google Scholar · View at Scopus
  108. H. Levkovitch-Verbin, S. Vander, and S. Melamed, “Rasagiline-induced delay of retinal ganglion cell death in experimental glaucoma in rats,” Journal of Glaucoma, vol. 20, no. 5, pp. 273–277, 2011. View at Publisher · View at Google Scholar · View at Scopus
  109. H. Levkovitch-Verbin, Y. Waserzoog, S. Vander, D. Makarovsky, and P. Ilia, “Minocycline mechanism of neuroprotection involves the Bcl-2 gene family in optic nerve transection,” International Journal of Neuroscience, vol. 124, no. 10, pp. 755–761, 2014. View at Publisher · View at Google Scholar · View at Scopus
  110. H. Wang, C. Zhang, D. Lu et al., “Oligomeric proanthocyanidin protects retinal ganglion cells against oxidative stress-induced apoptosis,” Neural Regeneration Research, vol. 8, no. 25, pp. 2317–2326, 2013. View at Google Scholar
  111. H. Cheng, Y. Ding, R. Yu, J. Chen, and C. Wu, “Neuroprotection of a novel cyclopeptide C∗HSDGIC∗ from the cyclization of PACAP (1–5) in cellular and rodent models of retinal ganglion cell apoptosis,” PLoS ONE, vol. 9, no. 10, Article ID e108090, 2014. View at Publisher · View at Google Scholar · View at Scopus
  112. Z. Wang, X. Pan, D. Wang et al., “Protective effects of protocatechuic acid on retinal ganglion cells from oxidative damage induced by H2O2,” Neurological Research, vol. 37, no. 2, pp. 159–166, 2014. View at Publisher · View at Google Scholar
  113. H. Marzban, M. R. Del Bigio, J. Alizadeh, S. Ghavami, R. M. Zachariah, and M. Rastegar, “Cellular commitment in the developing cerebellum,” Frontiers in Cellular Neuroscience, vol. 8, article 450, 2015. View at Publisher · View at Google Scholar
  114. P. Kermer, N. Klöcker, M. Labes, S. Thomsen, A. Srinivasan, and M. Bähr, “Activation of caspase-3 in axotomized rat retinal ganglion cells in vivo,” FEBS Letters, vol. 453, no. 3, pp. 361–364, 1999. View at Publisher · View at Google Scholar · View at Scopus
  115. P. Kermer, R. Ankerhold, N. Klöcker, S. Krajewski, J. C. Reed, and M. Bähr, “Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo,” Molecular Brain Research, vol. 85, no. 1-2, pp. 144–150, 2000. View at Publisher · View at Google Scholar · View at Scopus
  116. H. Levkovitch-Verbin, R. Dardik, S. Vander, and S. Melamed, “Mechanism of retinal ganglion cells death in secondary degeneration of the optic nerve,” Experimental Eye Research, vol. 91, no. 2, pp. 127–134, 2010. View at Publisher · View at Google Scholar · View at Scopus
  117. S. Choudhury, Y. Liu, A. F. Clark, and I.-H. Pang, “Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death,” Molecular Neurodegeneration, vol. 10, article 40, 2015. View at Publisher · View at Google Scholar
  118. V. Vigneswara, M. Berry, A. Logan, and Z. Ahmed, “Pharmacological inhibition of caspase-2 protects axotomised retinal ganglion cells from apoptosis in adult rats,” PLoS ONE, vol. 7, no. 12, Article ID e53473, 2012. View at Publisher · View at Google Scholar
  119. H. Levkovitch-Verbin, R. Dardik, S. Vander, Y. Nisgav, M. Kalev-Landoy, and S. Melamed, “Experimental glaucoma and optic nerve transection induce simultaneous upregulation of proapoptotic and prosurvival genes,” Investigative Ophthalmology and Visual Science, vol. 47, no. 6, pp. 2491–2497, 2006. View at Publisher · View at Google Scholar · View at Scopus
  120. H. Levkovitch-Verbin, S. Vander, D. Makarovsky, and F. Lavinsky, “Increase in retinal ganglion cells' susceptibility to elevated intraocular pressure and impairment of their endogenous neuroprotective mechanism by age,” Molecular Vision, vol. 19, pp. 2011–2022, 2013. View at Google Scholar · View at Scopus
  121. U. Wojda, E. Salinska, and J. Kuznicki, “Calcium ions in neuronal degeneration,” IUBMB Life, vol. 60, no. 9, pp. 575–590, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. R. M. Sappington, T. Sidorova, D. J. Long, and D. J. Calkins, “TRPV1: contribution to retinal ganglion cell apoptosis and increased intracellular Ca2+ with exposure to hydrostatic pressure,” Investigative Opthalmology & Visual Science, vol. 50, no. 2, pp. 717–728, 2009. View at Publisher · View at Google Scholar
  123. W. Huang, J. Fileta, I. Rawe, J. Qu, and C. L. Grosskreutz, “Calpain activation in experimental glaucoma,” Investigative Ophthalmology & Visual Science, vol. 51, no. 6, pp. 3049–3054, 2010. View at Publisher · View at Google Scholar
  124. W. Huang, J. B. Fileta, A. Dobberfuhl et al., “Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma,” Proceedings of the National Academy of Sciences, vol. 102, no. 34, pp. 12242–12247, 2005. View at Publisher · View at Google Scholar
  125. L. F. Gumy, C. L. Tan, and J. W. Fawcett, “The role of local protein synthesis and degradation in axon regeneration,” Experimental Neurology, vol. 223, no. 1, pp. 28–37, 2010. View at Publisher · View at Google Scholar
  126. V. T. Ribas and P. Lingor, “Calcium channel inhibition-mediated axonal stabilization improves axonal regeneration after optic nerve crush,” Neural Regeneration Research, vol. 11, no. 8, pp. 1245–1246, 2016. View at Publisher · View at Google Scholar
  127. J. Knoferle, J. C. Koch, T. Ostendorf et al., “Mechanisms of acute axonal degeneration in the optic nerve in vivo,” Proceedings of the National Academy of Sciences, vol. 107, no. 13, pp. 6064–6069, 2010. View at Publisher · View at Google Scholar
  128. M. Kerschensteiner, M. E. Schwab, J. W. Lichtman, and T. Misgeld, “In vivo imaging of axonal degeneration and regeneration in the injured spinal cord,” Nature Medicine, vol. 11, no. 5, pp. 572–577, 2005. View at Publisher · View at Google Scholar · View at Scopus
  129. N. E. Ziv and M. E. Spira, “Localized and transient elevations of intracellular Ca2+ induce the dedifferentiation of axonal segments into growth cones,” Journal of Neuroscience, vol. 17, no. 10, pp. 3568–3579, 1997. View at Google Scholar · View at Scopus
  130. D. Gitler and M. E. Spira, “Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation,” Neuron, vol. 20, no. 6, pp. 1123–1135, 1998. View at Publisher · View at Google Scholar · View at Scopus
  131. P. Lingor, J. C. Koch, L. Tönges, and M. Bähr, “Axonal degeneration as a therapeutic target in the CNS,” Cell and Tissue Research, vol. 349, no. 1, pp. 289–311, 2012. View at Publisher · View at Google Scholar