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.

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