Multifaceted role of MG53 in alleviating neuromuscular function decline in ALS

MG53 在缓解 ALS 神经肌肉功能衰退中的多方面作用

基本信息

批准号：
10681888
负责人：
Jianjie Ma
金额：
$ 67.44万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681888
关键词：
ALS patients Ablation Affect Amyotrophic Lateral Sclerosis Antioxidants Autophagocytosis Autophagosome Axon Back Benefits and Risks Biochemical Biology Blood Circulation Cardiolipins Cell membrane Cell physiology Cellular Structures Clinical Crossbreeding Data Defect Disease Disease Progression Dose Elements Equilibrium Extravasation FRAP1 gene Feedback Feeds Functional disorder Generations Genetic Goals Half-Life Human Imaging Device Injury Longevity Lysosomes Maintenance Mediating Membrane Methods Mitochondria Modeling Molecular Motor Cortex Motor Neurons Mus Muscle Muscle Cells Muscle Fibers Muscle Mitochondria Muscular Atrophy Nerve Neuroglia Neuromuscular Diseases Neuromuscular Junction Neurons Normal tissue morphology Oxidative Stress Oxidative Stress Induction Pathologic Pathology Pathway interactions Physiology Process Progressive Disease Protein Family Proteins Psoas Muscles Quality Control Reactive Oxygen Species Recombinants Regenerative capacity Regimen Research Research Design Respiratory Diaphragm Respiratory Failure Respiratory Muscles Role Safety Sampling Sarcolemma Serum Signal Transduction Site Skeletal Muscle Stress Support Groups Symptoms Systemic disease TRIM Motif Techniques Testing Therapeutic Therapeutic Effect Toxic effect Transgenic Mice Translating Visualization Withdrawal amyotrophic lateral sclerosis therapy base functional decline improved live cell imaging member mitochondrial dysfunction mortality mouse model multicatalytic endopeptidase complex muscle degeneration nerve supply neuromuscular function neuron loss novel novel therapeutics pharmacologic preservation regenerative tissue repair function repaired tissue regeneration tissue repair ubiquitin-protein ligase

ALS patients Ablation Affect Amyotrophic Lateral Sclerosis Antioxidants Autophagocytosis Autophagosome Axon Back Benefits and Risks Biochemical Biology Blood Circulation Cardiolipins Cell membrane Cell physiology Cellular Structures Clinical Crossbreeding Data Defect Disease Disease Progression Dose Elements Equilibrium Extravasation FRAP1 gene Feedback Feeds Functional disorder Generations Genetic Goals Half-Life Human Imaging Device Injury Longevity Lysosomes Maintenance Mediating Membrane Methods Mitochondria Modeling Molecular Motor Cortex Motor Neurons Mus Muscle Muscle Cells Muscle Fibers Muscle Mitochondria Muscular Atrophy Nerve Neuroglia Neuromuscular Diseases Neuromuscular Junction Neurons Normal tissue morphology Oxidative Stress Oxidative Stress Induction Pathologic Pathology Pathway interactions Physiology Process Progressive Disease Protein Family Proteins Psoas Muscles Quality Control Reactive Oxygen Species Recombinants Regenerative capacity Regimen Research Research Design Respiratory Diaphragm Respiratory Failure Respiratory Muscles Role Safety Sampling Sarcolemma Serum Signal Transduction Site Skeletal Muscle Stress Support Groups Symptoms Systemic disease TRIM Motif Techniques Testing Therapeutic Therapeutic Effect Toxic effect Transgenic Mice Translating Visualization Withdrawal amyotrophic lateral sclerosis therapy base functional decline improved live cell imaging member mitochondrial dysfunction mortality mouse model multicatalytic endopeptidase complex muscle degeneration nerve supply neuromuscular function neuron loss novel novel therapeutics pharmacologic preservation regenerative tissue repair function repaired tissue regeneration tissue repair ubiquitin-protein ligase

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项目摘要

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.

项目摘要肌萎缩性侧性硬化症（ALS）是一种神经肌肉疾病，其特征是运动神经元死亡和严重肌肉浪费；呼吸肌的失败是ALS患者死亡率的常见原因。而ALS是通常被认为是运动神经元的“垂死”过程，来自美国和其他研究小组支持肌肉似乎是ALS的主要目标，除了是轴突拔出的受害者。该项目建立在科学前提的基础上，即ALS是一种系统性氧化应激的疾病，会影响该疾病肌肉膜修复和质量控制的细胞过程，因此神经肌肉的完整性交界处（NMJ）为电动机之间的双向串扰提供了结构和功能框架神经元和肌肉纤维。我们发现ALS小鼠（SOD1G93A）diaphragm肌肉显示出增加在ALS符号发作之前发生的膜损伤。我们确定了局部膜修复 ALS肌肉NMJ附近的缺陷，在ALS发作之前，分段线粒体功能障碍疾病。在分子水平上，我们提供证据表明线粒体氧化应激会影响元素由MG53管辖的细胞膜修复过程，MG53是三方蛋白的成员在膜损伤部位的修复斑块组装成核中的基本作用。我们还发现肌肉修复受损，MG53聚集是人类ALS中的常见病理。重组人类MG53（RHMG53）蛋白质系统施用时，准备了肌膜损伤的修复和氧化应激减少，从而改善了NMJ神经支配并延长ALS小鼠的寿命。除了促进膜修复外，MG53还通过其内在的E3-参与自噬信号传导连接酶的活性有助于细胞质量控制，这可以反馈以保持膜完整性压力条件。这些发现支持MG53在减轻神经肌肉功能中的多面作用 ALS的下降。我们基于团队的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ALS中的肌膜脆性，（2）这些病理变化如何变化影响MG53的正常组织修复功能，（3）MG53正常功能的破坏如何反馈到恶化的组织修复和氧化应激，导致NMJ变性的恶性循环，（4）MG53的影响自噬途径的信号传导影响ALS中的细胞质量控制机械，以及（5）治疗外源施用RHMG53蛋白作为一种新型ALS治疗的潜在和风险效益。