Multifaceted role of MG53 in alleviating neuromuscular function decline in ALS

项目摘要 肌萎缩侧索硬化症(ALS)是一种以运动神经元死亡和严重的 肌肉萎缩；呼吸肌衰竭是肌萎缩侧索硬化症患者死亡的常见原因。而ALS是 我们和其他研究小组的研究通常被认为是运动神经元的“死亡向前”过程 支持肌肉似乎是肌萎缩侧索硬化症的主要目标，除了是轴突收缩的受害者。 该项目建立在ALS是一种系统性氧化应激疾病的科学前提之上，这种疾病会影响 肌膜修复的细胞过程和质量控制，从而神经肌肉的完整性 为电机之间的双向串扰提供结构和功能框架的结点(NMJ) 神经元和肌肉纤维。我们发现ALS小鼠(SOD1G93A)的横隔肌显示增加 在肌萎缩侧索硬化症症状出现之前发生的膜损伤。我们确定了局部的膜修复 ALS肌肉NMJ附近的缺陷，其中节段性线粒体功能障碍先于ALS的发病 疾病。在分子水平上，我们提供了线粒体氧化应激可以影响元素的证据 由MG53控制的细胞膜修复过程，MG53是提供服务的三方家族蛋白质的成员 在膜损伤部位修复补丁组装成核中的重要作用。我们还发现， 肌肉修复受损和MG53聚集是人类ALS的常见病理。重组人 人MG53(RhMG53)蛋白全身给药时，可促进肌膜损伤的修复和 减少氧化应激，从而改善NMJ神经支配，延长ALS小鼠的寿命。 除了促进膜修复外，MG53还通过其固有的E3- 连接酶活性有助于细胞质量控制，这可以反馈，以保持膜的完整性在 压力状态。这些发现支持MG53在减轻神经肌肉功能方面的多方面作用 肌萎缩侧索硬化症发病率下降。我们团队研究的长期目标是了解(1)肌肉线粒体是如何 功能障碍和氧化应激导致肌萎缩侧索硬化症的肌膜脆性，(2)这些病理变化是如何 影响MG53‘S正常组织修复功能；(3)MG53’S正常功能中断如何反馈 恶化组织修复和氧化应激，导致NMJ退变的恶性循环，(4)MG53的影响 影响肌萎缩侧索硬化症细胞质量控制机制的自噬途径信号，以及(5)治疗 外源性应用重组人MG53蛋白作为一种新的ALS治疗方法的潜力和风险收益。

Project Summary Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by motor neuron death and severe muscle wasting; failure of the respiratory muscle is a common cause of mortality in ALS patients. While ALS is generally considered as a “dying-forward” process of motor neurons, studies from us and other research groups support that muscle appears to be a primary target of ALS, in addition to being a victim of axonal withdrawal. This project builds on the scientific premise that ALS is a disease of systemic oxidative stress that impacts the cellular processof muscle membrane repair and quality control, and consequently integrity of the neuromuscular junction (NMJ) that provides the structural and functional framework for bidirectional crosstalk between motor neuron and muscle fibers. We discovered that the ALS mouse (SOD1G93A) diaphragm muscle displays increased membrane damage that occurs prior to the onset of ALS symptoms. We identified localized membrane repair defects near the NMJ of ALS muscle, where segmented mitochondria dysfunction precedes the onset of ALS disease. At the molecular level, we provide evidence that mitochondria-oxidative stress can affect the elemental process of cell membrane repair that is governed by MG53, a member of the tripartite family protein that serves essential roles in nucleating the assembly of repair patches at membrane injury sites. We also found that compromised muscle repair and MG53 aggregation is a common pathology in human ALS. The recombinant human MG53 (rhMG53) protein, when administered systemically, facilitated the repair of sarcolemma injury and reduced oxidative stress, consequently improving NMJ innervation and prolonging the lifespan of the ALS mice. In addition to facilitating membrane repair, MG53 also participates in autophagy signaling via its intrinsic E3- ligase activity to contribute to cellular quality control, which could feedback to preserve membrane integrity under stress condition. These findings support the multifaceted role of MG53 in alleviating neuromuscular function decline in ALS. The long-term goals of our team-based research are to understand (1) how muscle mitochondrial dysfunction and oxidative stress contribute to sarcolemma fragility in ALS, (2) how these pathological changes impact MG53’s normal tissue repair function, (3) how the disruption of MG53’s normal function feeds back to worsen tissue repair and oxidative stress, leading to a vicious cycle of NMJ degeneration, (4) the impact of MG53 signaling on autophagy pathway affecting the cellular quality control machinery in ALS, and (5) the therapeutic potential and risk-benefits of exogenously administrated rhMG53 protein as a novel ALS therapy.