CHARACTERIZATION OF A NOVEL MUSK BINDING PROTEIN

My long-term research goal is to understand the molecular mechanisms that regulate neuromuscular synapse formation and maintenance. Synapses form when a motor axon reaches a muscle fiber. Acetylcholine receptors become concentrated at the site of innervation and processes at the molecular and cellular level lead to the development of a mature and functional neuromuscular synapse. Agrin, an extracellular heparan proteoglycan produced by motor neurons, and MuSK, a muscle-specific kinase are the key players in neuromuscular synapse formation. The critical events during synapse formation include agrin-mediated activation of MuSK, concentration of MuSK at the synapse and tyrosine phosphorylation. Signal transduction downstream of MuSK regulates acetylcholine receptor clustering but the exact mechanism of action is unclear. In previous studies we have isolated a novel protein that binds to MuSK. This protein is localized at the neuromuscular synapse and is homolog to proteins with known functions during endocytosis. During the course of the proposed FWF research project we intend to characterize the newly identified protein and its role during MuSK trafficking and neuromuscular synapse development. In addition, accumulating evidence about cross-talk between endocytosis and signaling raised my interest to study the role of MuSK trafficking during neuromuscular synapse formation and maintenance. Very little is known about the regulation of MuSK protein localization, stability and turnover. I propose to study MuSK stability and endocytosis in detail. Experiments will determine whether MuSK trafficking is involved in neuromuscular synapse formation and whether it is linked to MuSK signaling.

My long-term research goal is to understand the molecular mechanisms that regulate neuromuscular synapse formation and maintenance. Synapses form when a motor axon reaches a muscle fiber. Acetylcholine receptors become concentrated at the site of innervation and processes at the molecular and cellular level lead to the development of a mature and functional neuromuscular synapse. Agrin, an extracellular heparan proteoglycan produced by motor neurons, and MuSK, a muscle-specific kinase are the key players in neuromuscular synapse formation. The critical events during synapse formation include agrin-mediated activation of MuSK, concentration of MuSK at the synapse and tyrosine phosphorylation. Signal transduction downstream of MuSK regulates acetylcholine receptor clustering but the exact mechanism of action is unclear. In previous studies we have isolated a novel protein that binds to MuSK. This protein is localized at the neuromuscular synapse and is homolog to proteins with known functions during endocytosis. During the course of the proposed FWF research project we intend to characterize the newly identified protein and its role during MuSK trafficking and neuromuscular synapse development. In addition, accumulating evidence about cross-talk between endocytosis and signaling raised my interest to study the role of MuSK trafficking during neuromuscular synapse formation and maintenance. Very little is known about the regulation of MuSK protein localization, stability and turnover. I propose to study MuSK stability and endocytosis in detail. Experiments will determine whether MuSK trafficking is involved in neuromuscular synapse formation and whether it is linked to MuSK signaling.