Identification of the Stress Which Causes Optineurin Aggregation

Satoshi Inagaki,Junko Seki,Hideaki Hara,Shinsuke Nakamura,Hideo Kaneko,Chizuru Kawase,Kazuki Ohuchi,Masamitsu Shimazawa,Michinori Funato,Shiori Ando

doi:10.4236/nm.2019.102010

Satoshi Inagaki, Junko Seki + Show 8 more

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https://doi.org/10.4236/nm.2019.102010

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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.

Highlights

Glaucoma is characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, and is one of the leading causes of irreversible blindness worldwide [1]
Identification of Stresses That Induce OPTN Aggregation To evaluate whether OPTN might aggregate in WT-Induced Pluripotent Stem Cells (iPSCs)-RGCs following the induction of pharmacological stresses related to RGC degeneration, we evaluated OPTN protein levels in the TNE buffer insoluble fraction, as previously described [17]
RGC death in patients with glaucoma or experimental animal models is related to elevated endoplasmic reticulum (ER) stress [27] [28] [29], increased excitatory glutamate [30] [31], tumor necrosis factor α (TNF-α) signaling [32] [33] [34] [35], oxidative stress [36], mitochondrial dysfunction [21] [36] [37], and abnormal autophagic flux [38] [39] [40]

Summary

Introduction

Glaucoma is characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, and is one of the leading causes of irreversible blindness worldwide [1]. Primary open-angle glaucoma (POAG) is the most common type of glaucoma. POAG is classified into two subsets: high tension glaucoma (HTG) and normal tension glaucoma (NTG). The only therapy currently available for POAG is the lowering of intraocular pressure (IOP). Some individuals develop glaucoma when their IOP is in the normal range [2] [3]. NTG is the major subtype that occurs in patients with glaucoma in Japan [4]. It has been suggested that glaucoma is caused by high IOP and by other, unknown risk factors in its pathology [5]

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