Investigation of Signals for Endocytosis of AChR Beta and Delta Subunits for Proper Neuromuscular System Function – NAWA2

To ensure proper functioning of the neuromuscular junction, acetylcholine receptors (AChRs) must be maintained at high density within the postsynaptic machinery. Loss of receptors at the synapse is observed in many incurable neuromuscular disorders of both genetic and autoimmune origin. It is assumed that receptor loss at synapses occurs via endocytosis; however, how this process is regulated at the molecular level remains largely unknown. Using bioinformatic tools, our team identified short amino acid sequences in the beta and delta subunits of AChRs that are likely responsible for binding to the AP2 protein complex, which links membrane proteins to clathrin and enables their internalization.

The aim of the project is to investigate whether the newly identified sequences in the beta and delta subunits indeed bind to the AP2 complex and regulate endocytosis of AChR receptors at synapses. Our research will constitute a fundamental contribution to understanding the organization of neuromuscular synapses and may support the development of new therapeutic strategies, for example targeting the inhibition of AChR receptor endocytosis in many neuromuscular diseases for which no effective therapy currently exists.