Abstract

Glaucoma is a neurodegenerative disease that leads to irrevocable blindness. In glaucoma, even though axonal damage and function deficit culminates in retinal ganglion cell (RGC) degeneration, our knowledge on the autophagic mechanisms and the role of specific microRNAs is still limited. In this study, we investigated the role of microRNA-124 (MiR-124) in surgically induced glaucomatous neurodegeneration using a mouse model. Animals were segregated into four cohorts of 10 each: (i) sham-operated (n = 10); (ii) surgically induced glaucoma (SIG; n = 10); (iii) SIG + miR-124 mimic; (iv) SIG + miR-NC. Chronic elevation of intraocular pressure (IOP) is a critical risk factor for glaucoma. In our study, chronically elevated IOP caused anterograde axonal transport (AAT) defect, increased the autophagic activity (manifested by significantly (p < 0.05) increased LC3-II/LC3-I ratio, beclin-1 and Atg7 protein expressions) and also downmodulated the protein expression of p-Akt and p-mTOR, mediated by the purinergic P2 receptor subtype 7 (P2X7) upmodulation—leading to retinal degeneration. However, administration of miR-124 mimic improved the retinal integrity and function, as indicated by the improved AAT function, normalized the autophagic dysfunction, modulated the protein expression of P2X7-mediated p-Akt and p-mTOR. Hence, we propose that development of miR-124-based advanced therapies might be a potential avenue in the treatment of glaucomatous neurodegeneration.

摘要

青光眼是一种神经退行性疾病，会导致不可逆转的失明。在青光眼中，尽管轴突损伤和功能缺陷最终导致视网膜神经节细胞 (RGC) 变性，但我们对自噬机制和特定 microRNA 作用的了解仍然有限。在这项研究中，我们使用小鼠模型研究了 microRNA-124 (MiR-124) 在手术诱导的青光眼神经变性中的作用。动物被分成四组，每组 10 只：（i）假手术（n  = 10）；(ii) 手术诱发的青光眼 (SIG; n = 10); (iii) SIG + miR-124 模拟物；(iv) SIG + miR-NC。眼内压（IOP）的慢性升高是青光眼的关键危险因素。在我们的研究中，长期升高的 IOP 导致顺行轴突运输 (AAT) 缺陷，增加自噬活性（表现为显着 ( p < 0.05) 增加 LC3-II/LC3-I 比值、beclin-1 和 Atg7 蛋白表达）并下调 p-Akt 和 p-mTOR 的蛋白表达，由嘌呤能 P2 受体亚型 7 (P2X7) 上调介导 - 领先到视网膜变性。然而，miR-124 模拟物的施用改善了视网膜的完整性和功能，如改善的 AAT 功能所示，使自噬功能障碍正常化，调节 P2X7 介导的 p-Akt 和 p-mTOR 的蛋白质表达。因此，我们建议开发基于 miR-124 的先进疗法可能是治疗青光眼神经变性的潜在途径。