Neuromuscular Junction

The Role of Rapsyn in the Formation of the Neuromuscular Junction and Disease
2008 Seed Grant
William Green, Ph.D.
University of Chicago

In the proposed research, we will examine the role specific domains of the protein rapsyn in the development of the neuromuscular junction (NMJ).  Rapsyn is part of the scaffolding on the postsynaptic side of the HNMJ and associates with nicotinic acetylcholine receptors (nAChRs), the postsynaptic receptors responsible for the rapid response to the release of the neurotransmitter, Ach.without rapsyn, NMJs on muscle in mice fail to form because nAChRs never arrive at the NMJ and mice die at birth.  Our preliminary data indicates that the RING domain of rapsyn is required for formation of the NMJ.  Interestingly, the RING domain of rapsyn does not appear to be involved in the interaction between rapsyn and nAChRs.  The RING domain on most other proteins is required for a specific enzymatic activity called ubiquitination.
Rapsyn has been implicated in different neurodegenerative diseases.  Several mutations in the rapsyn gene result in congenital myasthenic syndromes.  In addition, myasthenia gravis (MG) is caused by autoantibodies to nAChRs.  Binding of autoantibodies to nAChRs generated in the disease cause increased internalization of nAChRs and activate complement, both which lead to deterioration of the NMJ.  In animal models of MG, over expression of rapsyn provides resistance to the loss of surface receptor and ameliorates deterioration of the NMJ.  These results suggest that autoantibody binding to nAChRs affects rapsyn stability at the NMJ AND THAT rapsyn has a significant role in the pathology of MG as well as in congenital myasthenic syndromes.