Glaucoma is a common neurodegenerative disease that can cause blindness and occurs worldwide. Currently, lowering intraocular pressure is the only therapy available to protect retinal ganglion cells (RGCs). However, this therapy does not prevent RGC death in all patients. Therefore, new therapeutic approaches for glaucoma are urgently required, and neuroprotection of RGCs is a focus for many researchers. Optineurin (OPTN) is one of the normal tension glaucoma (NTG) relative genes, while mutant OPTN can form a characteristic aggregation, causing RGC death. Hence, elucidation of the mechanism of OPTN aggregation might provide a clue to help understand RGC death. To examine whether non-mutant OPTN could also aggregate, we pharmacologically induced some glaucoma-related stresses, such as endoplasmic reticulum (ER) stress, glutamate toxicity, activation of TNF-α signaling, mitochondrial dysfunction, and autophagic flux impairment. Our results showed that ER stress, TNF-α signaling, and autophagic flux are involved in OPTN aggregation. Furthermore, our data indicated that increased ER stress, activation of TNF-α signaling, and impaired autophagic flux induce OPTN aggregation, suggesting that OPTN aggregation might be an important therapeutic target not only for familial NTG with mutated OPTN but also for patients with glaucoma more generally.
References
[1]
Flaxman, S.R., Bourne, R.R.A., Resnikoff, S., Ackland, P., Braithwaite, T., Cicinelli, M.V., Das, A., Jonas, J.B., et al. (2017) Global Causes of Blindness and Distance Vision Impairment 1990-2020: A Systematic Review and Meta-Analysis. The Lancet Global Health, 5, e1221-e1234.
[2]
Kass, M.A., Heuer, D.K., Higginbotham, E.J., Johnson, C.A., Keltner, J.L., Miller, J.P., Parrish, R.K., et al. (2002) The Ocular Hypertension Treatment Study: A Randomized Trial Determines that Topical Ocular Hypotensive Medication Delays or Prevents the Onset of Primary Open-Angle Glaucoma. Archives of Ophthalmology, 120, 701-713. https://doi.org/10.1001/archopht.120.6.701
[3]
Collaborative Normal-Tension Glaucoma Study Group (1998) The Effectiveness of Intraocular Pressure Reduction in the Treatment of Normal-Tension Glaucoma. American Journal of Ophthalmology, 126, 498-505.
https://doi.org/10.1016/S0002-9394(98)00272-4
[4]
Iwase, A., Suzuki, Y., Araie, M., Yamamoto, T., Abe, H., Shirato, S., Kuwayama, Y., Mishima, H.K., Shimizu, H., Tomita, G., Inoue, Y. and Kitazawa, Y. (2004) The Prevalence of Primary Open-Angle Glaucoma in Japanese: The Tajimi Study. Ophthalmology, 111, 1641-1648. https://doi.org/10.1016/j.ophtha.2004.03.029
[5]
Naito, T., Fujiwara, M., Miki, T., Araki, R., Fujiwara, A., Shiode, Y., Morizane, Y., Nagayama, M. and Shiraga, F. (2017) Effect of Trabeculectomy on Visual Field Progression in Japanese Progressive Normal-Tension Glaucoma with Intraocular Pressure <15 mmHg. PLoS ONE, 12, e0184096.
https://doi.org/10.1371/journal.pone.0184096
[6]
Rezaie, T., Child, A., Hitchings, R., Brice, G., Miller, L., Coca-Prados, M., Heon, E., Krupin, T., Ritch, R., Kreutzer, D., Crick, R.P. and Sarfarazi, M. (2002) Adult-Onset Primary Open-Angle Glaucoma Caused by Mutations in Optineurin. Science, 295, 1077-1079. https://doi.org/10.1126/science.1066901
[7]
Aung, T., Rezaie, T., Okada, K., Viswanathan, A.C., Child, A.H., Brice, G., et al. (2005) Hitchings, Clinical Features and Course of Patients with Glaucoma with the E50K Mutation in the Optineurin Gene. Investigative Ophthalmology & Visual Science, 46, 2816-2822. https://doi.org/10.1167/iovs.04-1133
[8]
Tham, Y.C., Li, X., Wong, T.Y., Quigley, H.A., Aung, T. and Cheng, C.Y. (2014) Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040: A Systematic Review and Meta-Analysis. Ophthalmology, 121, 2081-2090.
https://doi.org/10.1016/j.ophtha.2014.05.013
[9]
Kumar, A., Basavaraj, M.G., Gupta, S.K., Qamar, I., Ali, A.M., Bajaj, V., et al. (2007) Role of CYP1B1, MYOC, OPTN, and OPTC Genes in Adult-Onset Primary Open-Angle Glaucoma: Predominance of CYP1B1 Mutations in Indian Patients. Molecular Vision, 13, 667-676.
Fuse, N., Takahashi, K., Akiyama, H., Nakazawa, T., Seimiya, M., et al. (2004) Molecular Genetic Analysis of Optineurin Gene for Primary Open-Angle and Normal Tension Glaucoma in the Japanese Population. Journal of Glaucoma, 13, 299-303.
https://doi.org/10.1097/00061198-200408000-00007
[12]
Weidberg, H. and Elazar, Z. (2011) TBK1 Mediates Crosstalk between the Innate Immune Response and Autophagy. Science Signaling, 4, pe39.
https://doi.org/10.1126/scisignal.2002355
[13]
Wild, P., Farhan, H., McEwan, D.G., Wagner, S., Rogov, V.V., Brady, N.R., et al. (2011) Phosphorylation of the Autophagy Receptor Optineurin Restricts Salmonella Growth. Science, 333, 228-233. https://doi.org/10.1126/science.1205405
[14]
Sudhakar, C., Nagabhushana, A., Jain, N. and Swarup, G. (2009) NF-kB Mediates Tumor Necrosis Factor Alpha-Induced Expression of Optineurin, a Negative Regulator of NF-kB. PLoS ONE, 4, e5114. https://doi.org/10.1371/journal.pone.0005114
[15]
Zhu, G., Wu, C.J., Zhao, Y. and Ashwell, J.D. (2007) Optineurin Negatively Regulates TNFα-Induced NF-kB Activation by Competing with NEMO for Ubiquitinated RIP. Current Biology, 17, 1438-1443. https://doi.org/10.1016/j.cub.2007.07.041
[16]
Sirohi, K., Chalasani, M.L., et al. (2013) M98K-OPTN Induces Transferrin Receptor degradation and RAB12-Mediated Autophagic Death in Retinal Ganglion Cells. Autophagy, 9, 510-527. https://doi.org/10.4161/auto.23458
[17]
Minegishi, Y., Iejima, D., Kobayashi, H., Chi, Z.L., et al. (2013) Enhanced Optineurin E50K-TBK1 Interaction Evokes Protein Insolubility and Initiates Familial Primary Open-Angle Glaucoma. Human Molecular Genetics, 22, 3559-3567.
https://doi.org/10.1093/hmg/ddt210
[18]
Minegishi, Y., Nakayama, M., Iejima, D., Kawase, K. and Iwata, T. (2016) Significance of Optineurin Mutations in Glaucoma and Other Diseases. Progress in Retinal and Eye Research, 55, 149-181. https://doi.org/10.1016/j.preteyeres.2016.08.002
[19]
Chalasani, M.L., Kumari, A., Radha, V. and Swarup, G. (2014) E50K-OPTN-Induced Retinal Cell Death Involves the Rab GTPase-Activating Protein, TBC1D17 Mediated Block in Autophagy. PLoS ONE, 9, e95758.
https://doi.org/10.1371/journal.pone.0095758
[20]
Inagaki, S., Kawase, K., Funato, M., Seki, J., Kawase, C., et al. (2018) Effect of Timolol on Optineurin Aggregation in Transformed Induced Pluripotent Stem Cells Derived From Patient with Familial Glaucoma. Investigative Ophthalmology & Visual Science, 59, 2293-2304. https://doi.org/10.1167/iovs.17-22975
[21]
Shim, M.S., Takihara, Y., Kim, K.Y., et al. (2016) Mitochondrial Pathogenic Mechanism and Degradation in Optineurin E50K Mutation-Mediated Retinal Ganglion Cell Degeneration. Scientific Reports, 6, Article No. 33830.
https://doi.org/10.1038/srep33830
[22]
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., et al. (2007) Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell, 131, 861-872. https://doi.org/10.1016/j.cell.2007.11.019
[23]
Kondo, T., Asai, M., Tsukita, K., Kutoku, Y., et al. (2013) Modeling Alzheimer’s disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aβ and Differential Drug Responsiveness. Cell Stem Cell, 12, 487-496.
https://doi.org/10.1016/j.stem.2013.01.009
[24]
Yoshida, M., Kitaoka, S., Egawa, N., Yamane, M., et al. (2015) Modeling the Early Phenotype at the Neuromuscular Junction of Spinal Muscular Atrophy Using Patient-Derived iPSCs. Stem Cell Reports, 4, 561-568.
https://doi.org/10.1016/j.stemcr.2015.02.010
[25]
Tucker, B.A., Solivan-Timpe, F., Roos, B.R., Anfinson, K.R., et al. (2014) Duplication of TBK1 Stimulates Autophagy in iPSC-Derived Retinal Cells from a Patient with Normal Tension Glaucoma. Journal of Stem Cell Research & Therapy, 3, 161.
https://doi.org/10.4172/2157-7633.1000161
[26]
Xie, B.B., Zhang, X.M., Hashimoto, T., Tien, A.H., Chen, A., Ge, J. and Yang, X.J. (2014) Differentiation of Retinal Ganglion Cells and Photoreceptor Precursors from Mouse Induced Pluripotent Stem Cells Carrying an Atoh7/Math5 Lineage Reporter. PLoS ONE, 9, e112175. https://doi.org/10.1371/journal.pone.0112175
[27]
Yang, X., Luo, C., et al. (2011) Neurodegenerative and Inflammatory Pathway Components Linked to TNF-alpha/TNFR1 Signaling in the Glaucomatous Human Retina. Investigative Ophthalmology & Visual Science, 52, 8442-8454.
https://doi.org/10.1167/iovs.11-8152
[28]
Ojino, K., Shimazawa, M., et al. (2015) Involvement of Endoplasmic Reticulum Stress in Optic Nerve Degeneration after Chronic High Intraocular Pressure in DBA/2J Mice. Journal of Neuroscience Research, 93, 1675-1683.
https://doi.org/10.1002/jnr.23630
[29]
Shimazawa, M., et al. (2007) Involvement of ER Stress in Retinal Cell Death. Molecular Vision, 13, 578-587.
[30]
Lipton, S.A. and Rosenberg, P.A. (1994) Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders. The New England Journal of Medicine, 330, 613-622. https://doi.org/10.1056/NEJM199403033300907
[31]
Harada, T., Harada, C., Nakamura, K., et al. (2007) The Potential Role of Glutamate Transporters in the Pathogenesis of Normal Tension Glaucoma. The Journal of Clinical Investigation, 117, 1763-1770. https://doi.org/10.1172/JCI30178
Tezel, G., Li, L.Y., Patil, R.V. and Wax, M.B. (2001) TNF-α and TNF-α Receptor-1 in the Retina of Normal and Glaucomatous Eyes. Investigative Ophthalmology & Visual Science, 42, 1787-1794.
[34]
Tezel, G. (2008) TNF-α Signaling in Glaucomatous Neurodegeneration. Progress in Brain Research, 173, 409-421. https://doi.org/10.1016/S0079-6123(08)01128-X
[35]
Nakazawa, T., Nakazawa, C., Matsubara, A., et al. (2006) Tumor Necrosis Factor-α Mediates Oligodendrocyte Death and Delayed Retinal Ganglion Cell Loss in a Mouse Model of Glaucoma. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 26, 12633-12641.
https://doi.org/10.1523/JNEUROSCI.2801-06.2006
[36]
Pinazo-Durán, M.D., Zanón-Moreno, V., Gallego-Pinazo, R. and García-Medina, J.J. (2015) Oxidative Stress and Mitochondrial Failure in the Pathogenesis of Glaucoma Neurodegeneration. Progress in Brain Research, 220, 127-153.
https://doi.org/10.1016/bs.pbr.2015.06.001
[37]
Leruez, S., Marill, A., Bresson, T., de Saint Martin, G., et al. A. (2018) A Metabolomics Profiling of Glaucoma Points to Mitochondrial Dysfunction, Senescence, and Polyamines Deficiency. Biochemistry and Molecular Biology, 59, 4355-4361.
https://doi.org/10.1167/iovs.18-24938
[38]
Deng, S., Wang, M., Yan, Z., Tian, Z., et al. (2013) Autophagy in Retinal Ganglion Cells in a Rhesus Monkey Chronic Hypertensive Glaucoma Model. PLoS ONE, 8, e77100. https://doi.org/10.1371/journal.pone.0077100
[39]
Park, H.Y., Kim, J.H. and Park, C.K. (2012) Activation of Autophagy Induces Retinal Ganglion Cell Death in a Chronic Hypertensive Glaucoma Model. Cell Death & Disease, 3, e290. https://doi.org/10.1038/cddis.2012.26
[40]
Russo, R., Nucci, C., Corasaniti, M.T., Bagetta, G. and Morrone, L.A. (2015) Autophagy Dysregulation and the Fate of Retinal Ganglion Cells in Glaucomatous Optic Neuropathy. Progress in Brain Research, 220, 87-105.
https://doi.org/10.1016/bs.pbr.2015.04.009
[41]
Hu, X., Dai, Y. and Sun, X. (2017) Parkin Overexpression Protects Retinal Ganglion Cells against Glutamate Excitotoxicity. Molecular Vision, 23, 447-456.
Kamalden, T.A., Ji, D. and Osborne, N.N. (2012) Rotenone-Induced Death of RGC-5 Cells Is Caspase Independent, Involves the JNK and p38 Pathways and Is Attenuated by Specific Green Tea Flavonoids. Neurochemical Research, 37, 1091-1101.
https://doi.org/10.1007/s11064-012-0713-5
[44]
Han, M.L., Liu, G.H., Guo, J., Yu, S.J. and Huang, J. (2016) Imipramine Protects Retinal Ganglion Cells from Oxidative Stress through the Tyrosine Kinase Receptor B Signaling Pathway. Neural Regeneration Research, 11, 476-479.
https://doi.org/10.4103/1673-5374.179066
[45]
Bansal, M., Swarup, G. and Balasubramanian, D. (2015) Functional Analysis of Optineurin and Some of Its Disease-Associated Mutants. IUBMB Life, 67, 120-128.
https://doi.org/10.1002/iub.1355
[46]
Delhase, M., Kim, S.Y., Lee, H., et al. (2012) TANK-Binding Kinase 1 (TBK1) Controls Cell Survival through PAI-2/SerpinB2 and Transglutaminase 2. Proceedings of the National Academy of Sciences of the United States of America, 109, E177-E186.
https://doi.org/10.1073/pnas.1119296109
[47]
Ying, H., Shen, X., Park, B. and Yue, B.Y. (2010) Posttranslational Modifications, Localization, and Protein Interactions of Optineurin, the Product of a Glaucoma gene. PLoS ONE, 5, e9168. https://doi.org/10.1371/journal.pone.0009168
[48]
Medinas, D.B., Rozas, P., Martinez Traub, F., et al. (2018) Endoplasmic Reticulum Stress Leads to Accumulation of Wild-Type SOD1 Aggregates Associated with Sporadic Amyotrophic Lateral Sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 115, 8209-8214.
https://doi.org/10.1073/pnas.1801109115
[49]
Korac, J., Schaeffer, V., Kovacevic, I., Clement, A.M., et al. (2013) Dikic, Ubiquitin-Independent Function of Optineurin in Autophagic Clearance of Protein Aggregates. Journal of Cell Science, 126, 580-592.
https://doi.org/10.1242/jcs.114926
