A novel neuroprotective role of optic atrophy 1 protein

视神经萎缩1蛋白的新神经保护作用

• 批准号: 10246780
• 负责人: YISANG YOON
• 金额: $ 22.41万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246780
• 关键词: Attenuated; Autosomal Dominant Optic Atrophy; Blindness; Cell Death; Cell Survival; Cells; Cessation of life; Child; Cleaved cell; Competence; Crista ampullaris; Cytoprotection; Data; Gene Transfer; Genes; Glaucoma; Health; Homocysteine; Hyperhomocysteinemia; In Vitro; Inherited; Inner mitochondrial membrane; Light; Literature; Maintenance; Mediating; Membrane; Mitochondria; Molecular; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Natural regeneration; Nutrient Depletion; Optic Atrophy; Optic Nerve; Oxidants; Oxidative Stress; Pathologic; Pathology; Permeability; Play; Proteins; Reactive Oxygen Species; Regulation; Resistance; Retina; Retinal Ganglion Cells; Role; Stress; Structure; Supporting Cell; System; Testing; Therapeutic; Time; Transmembrane Domain; Virus; base; design; excitotoxicity; functional restoration; ganglion cell; improved; in vivo; mitochondrial dysfunction; neuroprotection; novel; novel therapeutic intervention; optic nerve disorder; prevent; repaired; retinal ganglion cell degeneration; retinal neuron; stem cells; young adult

Project summary Degeneration of retinal ganglion cells (RGCs) is the major cause for blindness in optic neuropathies and glaucoma. The degenerated RGCs cannot be repaired, and currently, there are no treatments that regenerate RGCs. Stem cell-derived RGC replacement is likely the only treatment option; however, functional restoration of retina remains challenging and difficult. Neuroprotection is a more practical approach that prevents RGC degeneration and prolongs RGC survival, which can delay vision loss. Retina and optic nerve represent highly energy-demanding systems, requiring proper mitochondrial function. One of the mechanisms of RGC death is excitotoxicity that induces mitochondrial permeability transition (MPT), leading to mitochondrial dysfunction and RGC degeneration. The protein optic atrophy 1 (OPA1) plays a critical role in maintaining mitochondrial function, as mutations in OPA1 gene causes hereditary autosomal dominant optic atrophy. OPA1 is known to have a dual function, mediating fusion of mitochondrial inner membrane (IM) and maintaining cristae structure. In mitochondria, OPA1 exists as IM-anchored long L-OPA1 and short soluble S-OPA1 that is generated by a cleavage of L-OPA1. Although S-OPA1 had been considered a functionally insignificant cleavage product, our recent study demonstrated that S-OPA1 is competent for maintaining mitochondrial function. Importantly, our ongoing studies obtained new evidence that S-OPA1 renders improved cell survival under stress conditions by decreasing MPT. Therefore, in this proposal, we will define the new OPA1 mechanism for regulating MPT and explore its potential application for RGC neuroprotective therapy. Our central hypothesis is that S-OPA1 supports RGC survival under excitotoxic stress by decreasing MPT. We propose two specific aims to test our hypothesis. In Aim 1, we will determine the molecular mechanisms by which L- and S-OPA1 regulate MPT sensitivity. Using L- and S-OPA1-specific cells, we will alter OPA1 cleavage and oligomerization, and evaluate how they change MPT sensitivity and cell death. In aim 2, we will determine whether increasing the S-OPA1 level improves RGC survival under stress. Using virus-mediated gene transfer, we will test the effects of changing the levels of L- and S-OPA1 on RGC survival under excitotoxic stress in vitro and in vivo. This proposal is designed to define a new, third role of OPA1, as an MPT regulator, and to test its therapeutic potential for neuroprotective therapy. New information from the proposed studies will add a novel paradigm to the current understanding of OPA1 function and MPT regulation, and help developing a new strategy for ameliorating RGC degeneration.

项目摘要 视网膜神经节细胞（RGC）的变性是视力神经病和 青光眼。退化的RGC无法修复，目前，没有任何治疗方法可以再生 RGCS。干细胞衍生的RGC替代可能是唯一的治疗选择。但是，功能恢复 视网膜仍然具有挑战性和困难。神经保护是一种更实用的方法，可防止RGC 退化和延长RGC存活，这可能会延迟视力丧失。视网膜和视神经高度代表 能量要求系统，需要适当的线粒体功能。 RGC死亡的机制之一是 诱导线粒体通透性转变（MPT）的兴奋性毒性，导致线粒体功能障碍和 RGC变性。蛋白质眼萎缩1（OPA1）在维持线粒体功能中起关键作用， 随着OPA1基因的突变导致遗传常染色体显性视神经萎缩。 OPA1众所周知有双重 功能，介导线粒体内膜（IM）的融合并保持Cristae结构。在 线粒体，OPA1作为Im-Chard的长L-OPA1和短的可溶性S-OPA1存在，它是由A产生的 L-OPA1的裂解。尽管S-OPA1被认为是功能上微不足道的裂解产品，但我们 最近的研究表明，S-OPA1有能力维持线粒体功能。重要的是，我们的 正在进行的研究获得了新的证据，表明S-OPA1在应力条件下通过 减少MPT。因此，在此提案中，我们将定义用于调节MPT和的新的OPA1机制 探索其对RGC神经保护疗法的潜在应用。我们的中心假设是S-OPA1支持 通过减少MPT，在兴奋性应激下的RGC存活率。我们提出了两个特定的目的来检验我们的假设。 在AIM 1中，我们将确定L-和S-OPA1调节MPT敏感性的分子机制。使用 L-和S-OPA1特异性细胞，我们将改变OPA1的裂解和低聚，并评估它们如何改变 MPT敏感性和细胞死亡。在AIM 2中，我们将确定提高S-OPA1水平是否可以改善RGC 在压力下生存。使用病毒介导的基因转移，我们将测试改变L和L和 S-OPA1在体外和体内兴奋性毒性应激下的RGC存活率上。该建议旨在定义一个新的 OPA1作为MPT调节剂的第三个作用，并测试其神经保护疗法的治疗潜力。新的 拟议研究的信息将为OPA1功能的当前理解增加新的范式 和MPT调节，并帮助制定一种改善RGC退化的新策略。