Multifaceted role of MG53 in alleviating neuromuscular function decline in ALS

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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.