A cell culture model for Muscle Specific Kinase myasthenia gravis
The postsynaptic membrane of the neuromuscular junction (NMJ) is organized by Muscle specific tyrosine kinase (MuSK). This project will investigate the mechanisms that organize the MuSK membrane scaffold and how they are affected by diseases that cause NMJ failure.
MuSK is the core of a receptor tyrosine kinase protein complex including neural agrin, LRP4, and DOK7 that organises the NMJ. During development, MuSK assembles spontaneously into discrete membrane domains that serve as templates for assembling acetylcholine receptors and other components of the specialized postsynaptic membrane. Thus the MuSK membrane scaffold is critical for the formation and plasticity of the NMJ. Mutations and autoimmune antibodies that interfere with MuSK signalling cause disruption of the NMJ and muscle weakness.
This project will use recombinant MuSK and advanced fluorescence microscopy in cell culture to study the mechanisms of MuSK scaffold formation and modification. It will then investigate precisely how autoimmune antibodies and genetic mutations disrupt the postsynaptic MuSK scaffold to cause disease. The cell culture model created by this project will then be used as a first test for potential new therapeutic agents.Phillips WD, Christadoss P, Losen M, Punga A, Shigemoto K, Verschuuren J & Vincent A. (2015). Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis. Experimental Neurology 270, 29-40.
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The opportunity ID for this research opportunity is: 672
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