Neuromuscular Junction

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.

Other Grants

Lindsay M. De Biase, Ph.D., University of California Los Angeles
The Role of Microglial Lysosomes in Selective Neuronal Vulnerability
Synapses, the sites of signaling between neurons in the brain, play essential roles in learning, memory, and the health of neurons themselves. An enduring mystery is why some neurons are…
How the Nervous System Constructs Internal Models of the External World
As animals navigate their environments, they construct internal models of the external sensory world and use these models to guide their behavior. This ability to incorporate ongoing sensory stimuli into…
Xiaojing Gao, Ph.D., Stanford University
When Neural Circuits Meet Molecular Circuits: Quantitative Genetic Manipulation with Single-cell Consistency
Cells are the building blocks of our bodies. We get sick when the cells “misbehave”. The way modern gene therapies work is to introduce genes, fragments of DNA molecules that…
Rafiq Huda, Ph.D., Rutgers University
Conducting the Orchestra of Movement—Functional Role of Striatal Astrocytes in Health and Disease
Movement requires coordinated activity across a large brain-wide network. The striatum is a particularly important part of this circuit; it integrates motor-related information from many distinct brain regions to regulate…