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.
The maintenance of neuromuscular synapses requires a complex exchange of signals between motor neurons and muscle fibers, stabilizing the highly specialized postsynaptic membrane and the highly differentiated nerve terminal. Agrin, Lrp4, MuSK and Dok-7 are required to maintain neuromuscular synapses, and a reduction in their expression or activity may be responsible for the simplification of nerve terminals and the postsynaptic membrane during aging. The experiments described here are designed to determine whether Agrin/Lrp4/MuSK signaling becomes attenuated during aging, whether this decline contributes to synaptic deterioration and whether an agonist antibody to MuSK can preserve neuromuscular synapses.
| Burden, Steven J; Huijbers, Maartje G; Remedio, Leonor (2018) Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses. Int J Mol Sci 19: |
