Identification of the Stress Which Causes Optineurin Aggregation

Satoshi Inagaki, M. Funato, Junko Seki, Chizuru Kawase, Kazuki Ohuchi, Shiori Ando, Shinsuke Nakamura, M. Shimazawa, Hideo Kaneko, H. Hara
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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.
导致优神经蛋白聚集的压力的鉴定
青光眼是一种常见的神经退行性疾病,可导致失明,在世界各地都有发生。目前,降低眼压是唯一可用于保护视网膜神经节细胞(RGCs)的治疗方法。然而,这种疗法并不能预防所有患者的RGC死亡。因此,迫切需要新的治疗青光眼的方法,而RGCs的神经保护作用是许多研究者关注的焦点。OPTN是正常张力性青光眼(NTG)的相关基因之一,而突变的OPTN可形成特征性聚集,导致RGC死亡。因此,阐明OPTN聚集机制可能为理解RGC死亡提供线索。为了研究非突变的OPTN是否也能聚集,我们从药理学上诱导了一些与青光眼相关的应激,如内质网应激、谷氨酸毒性、TNF-α信号激活、线粒体功能障碍和自噬通量损伤。我们的研究结果表明内质网应激、TNF-α信号和自噬通量参与了OPTN聚集。此外,我们的数据表明内质网应激增加、TNF-α信号激活和自噬通量受损可诱导OPTN聚集,这表明OPTN聚集可能不仅是OPTN突变的家族性NTG的重要治疗靶点,也可能是更普遍的青光眼患者的重要治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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