NEW APPROACHES TO THE MECHANISM AND THERAPY FOR MYASTHENIA GRAVIS

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DESCRIPTION (provided by applicant): Myasthenia gravis is a neurological disorder characterized by weakness and fatigability of the skeletal muscles. Autoimmune antibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction (NMJ) are known to be the main cause of the disease. The AChR is a ligand-gated ion channel that mediates the transmission of electric signals from motor nerve to muscle. About two-thirds of autoimmune antibodies from sera of patients with myasthenia gravis bind to the Main Immunogenic Region (MIR), an epitope located on the extracellular domain of the alpha subunit of AChR. The antibodies cross-link the AChRs on muscle cell membrane, resulting in an increased rate of internalization/degradation of the receptor and impaired neuromuscular transmission. Current treatments for myasthenia gravis can only temporarily relieve symptoms. They are usually non-specific and cannot change the cause of the disease. The long-term goal of our research is to identify new drugs that can act more effectively with fewer side-effects for myasthenia gravis. In this R21 grant application, large quantities of the N-terminal, extracellular domain of alpha subunit of human muscle AChR will be generated in a yeast expression system. The receptor fragment will be crystallized in complex with mAb35, a reference monoclonal antibody that can cause experimental myasthenia gravis. The three-dimensional structure of the protein complex will be determined by x-ray diffraction. The structural information will be key to rational design of drugs that can prevent binding of autoimmune antibodies to AChR. PUBLIC HEALTH RELEVANCE This study should provide new insight into the molecular structure of a complex formed between the nicotinic acetylcholine receptor and autoimmune antibodies that causes myasthenia gravis, a relatively common neurological disease. The coordinates of the protein crystal structure will aid greatly the rational design of more potent and specific drugs as well as for understanding the role of a particular biochemical process in the development of myasthenia gravis. If successful, the exploratory study outlined in this R21 grant application may open a new avenue for future drug discovery aimed at effective control of the disease in patients.