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Identification of the Stress Which Causes Optineurin Aggregation

¹ Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
² Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan
³ Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan
⁴ Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan
⁵ Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
⁶ Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
⁷ Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
⁸ Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
⁹ Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan
¹⁰ Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

Neuroscience and Medicine·Volume 10 (2019)·Pages 150–161·Published 19 April 2019·DOI10.4236/nm.2019.102010

Abstract

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.

KeywordsGlaucomaInduced Pluripotent Stem CellsRetinal Ganglion CellsOptineurinProtein Aggregation

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Identification of the Stress Which Causes Optineurin Aggregation

Abstract

References (49)