Author(s)

Satoshi Inagaki^1,2, Michinori Funato², Junko Seki², Chizuru Kawase², Kazuki Ohuchi^1,2, Shiori Ando^1,2, Shinsuke Nakamura¹, Masamitsu Shimazawa^1*, Hideo Kaneko², Hideaki Hara¹

¹Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
²Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan.

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.

Glaucoma, Induced Pluripotent Stem Cells, Retinal Ganglion Cells, Optineurin, Protein Aggregation

Inagaki, S. , Funato, M. , Seki, J. , Kawase, C. , Ohuchi, K. , Ando, S. , Nakamura, S. , Shimazawa, M. , Kaneko, H. and Hara, H. (2019) Identification of the Stress Which Causes Optineurin Aggregation. Neuroscience and Medicine, 10, 150-161. doi: 10.4236/nm.2019.102010.