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神经肌肉疾病， 肌肉萎缩;呼吸肌衰竭是ALS患者死亡的常见原因。虽然ALS是 通常被认为是运动神经元的“死亡向前”过程，我们和其他研究小组的研究 除了成为轴突撤回受害者之外，支持肌肉似乎是ALS的主要目标。 该项目建立在ALS是一种全身性氧化应激疾病的科学前提上， 肌肉膜修复和质量控制的细胞过程，以及神经肌肉的完整性 连接（NMJ），为电机之间的双向串扰提供结构和功能框架 神经元和肌肉纤维。我们发现ALS小鼠（SOD 1G 93 A）膈肌显示增加， 在ALS症状发作之前发生的膜损伤。我们发现局部膜修复 ALS肌肉NMJ附近的缺陷，其中分段线粒体功能障碍先于ALS发作 疾病在分子水平上，我们提供的证据表明，氧化应激可以影响元素 由MG 53控制的细胞膜修复过程，MG 53是三重家族蛋白质的成员， 在膜损伤部位成核修复补片组装中的重要作用。我们还发现 受损的肌肉修复和MG 53聚集是人ALS中的常见病理。重组 人MG 53（rhMG 53）蛋白，当全身给药时，促进肌膜损伤的修复， 减少氧化应激，从而改善NMJ神经支配并延长ALS小鼠的寿命。 除了促进膜修复外，MG 53还通过其内在的E3-受体参与自噬信号传导。 连接酶活性有助于细胞质量控制，这可以反馈以在细胞生长过程中保持膜完整性。 应力条件这些发现支持MG 53在减轻神经肌肉功能方面的多方面作用。 ALS的下降。我们团队研究的长期目标是了解（1）肌肉线粒体如何 功能障碍和氧化应激有助于肌膜脆性在ALS，（2）这些病理变化如何 影响MG 53的正常组织修复功能，（3）MG 53正常功能的破坏如何反馈到 恶化组织修复和氧化应激，导致NMJ退化的恶性循环，（4）MG 53的影响 自噬途径上的信号传导影响ALS中的细胞质量控制机制，和（5）治疗性 外源性rhMG 53蛋白作为一种新型ALS治疗的潜在和风险-效益。

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.