The effect of muscle-specific anchoring protein on the biology of the Neuromuscular system

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Stable and efficient synaptic transmission depends largely on the maintenance of a high number/density of postsynaptic receptors at synaptic sites. At the neuromuscular junction (NMJ), the synapse between spinal motor neurons and skeletal muscle cells, the mechanisms that regulate the stability of postsynaptic nicotinic acetylcholine receptors (AChRs) over the lifetime of animals remain largely unknown. Recent studies from our lab showed that αkap, a non-kinase muscle anchoring protein encoded within the calcium/calmodulin kinase II α gene, plays an important role in regulating the stability of nicotinic acetylcholine receptors (AChRs) and the structural integrity of the NMJ. In view of these results, we propose in the first aim to investigate the effect of αkap knockdown during the development of healthy neuromuscular synapses. In the second aim we propose to investigate the effect of the gain of function of αkap on the maturation and maintenance of compromised NMJs using mice deficient in the sub- complex of the dystrophin glycoprotein complex (DGC) (α-syntrophin and α-dystrobrevin). In the third aim we propose to investigate the molecular mechanistic link between the DGC sub- complex/αkap/ the deubiquitinating protease USP9X and the stability of AChR stability in mice deficient in α-syntrophin/α-dystrobrevin, and USP9X. The outcomes of these studies will be relevant for many neuromuscular diseases where the number and density of AChRs are compromised.