THE ROLE OF AGRIN/LRP4/MUSK/DOK-7 SIGNALING IN DISASSEMBLY OF NEUROMUSCULAR SYNAPSES DURING AGING.

 描述（由申请人提供）：神经肌肉突触的形成和维持需要运动神经元和肌纤维之间的相互信号交换，这对于高度特化的突触后膜和高度分化的神经末梢的组装和稳定性是必不可少的，对于快速、稳健和可靠的突触传递是至关重要的。聚集蛋白、Lrp 4、MuSK和Dok-7是形成和维持神经肌肉突触所必需的。因此，其表达或活性的降低可能是衰老期间神经末梢的简化和丢失以及突触后膜的解体的原因。一个有吸引力的假说表明，蛋白水解裂解的聚集蛋白，释放C-末端Lrp 4结合区的聚集蛋白从突触间隙，有助于在老化过程中的突触解体。我们将在第一个目标中直接测试这个想法。在第二个目标中，我们将确定其他关键信号成分Lrp 4，MuSK和Dok-7的表达以及MuSK酪氨酸磷酸化水平是否在衰老过程中下降。在第三个目标中，我们将确定用MuSK的激动剂抗体增强突触信号传导是否会减缓或阻止衰老过程中神经肌肉突触的退化，所述激动剂抗体刺激MuSK酪氨酸磷酸化，而不依赖于聚集蛋白和Lrp 4。这里描述的实验应该提供新的见解控制突触拆卸在衰老过程中的机制，并有可能确定一种新的治疗策略，以保持神经肌肉突触的结构和功能，减少肌肉减少症。

 DESCRIPTION (provided by applicant): The formation and maintenance of neuromuscular synapses requires a mutual exchange of signals between motor neurons and muscle fibers, which is essential for the assembly and stability of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal, critical for fast, robust and reliable synaptic transmission. Agrin, Lrp4, MuSK and Dok-7 are required both to form and to maintain neuromuscular synapses. As such, a reduction in their expression or activity may be responsible for the simplification and loss of nerve terminals and disassembly of the postsynaptic membrane during aging. One attractive hypothesis suggests that proteolytic cleavage of Agrin, releasing the C-terminal Lrp4-binding region of Agrin from the synaptic cleft, contributes to synaptic disassembly during aging. We will directly test this idea in the first aim.In the second aim, we will determine whether the expression of other key signaling components, Lrp4, MuSK and Dok-7, as well as the level of MuSK tyrosine phosphorylation, decreases during aging. In the third aim, we will determine whether boosting synaptic signaling with an agonist antibody to MuSK, which stimulates MuSK tyrosine phosphorylation independent of Agrin and Lrp4, slows or halts the deterioration of neuromuscular synapses during aging. The experiments described here should provide new insights into the mechanisms that control synaptic disassembly during aging and have the potential to identify a novel therapeutic strategy for preserving the structure and function of neuromuscular synapses and reducing sarcopenia.