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

稳定和有效的突触传递在很大程度上取决于维持高水平的 突触部位突触后受体的数量/密度。在神经肌肉交界处 脊髓运动神经元和骨骼肌细胞之间的突触，其机制 调节突触后烟碱型乙酰胆碱受体(AChRs)在 动物的寿命在很大程度上仍然不得而知。我们实验室最近的研究表明，αkap，一种 钙/钙调蛋白激酶IIα基因编码的非激活型肌肉锚定蛋白， 在调节烟碱型乙酰胆碱受体(AChRs)的稳定性方面起着重要作用 以及NMJ的结构完整性。鉴于这些结果，我们在第一个目标中建议 αKAP基因敲除在健康神经肌肉发育中的作用 突触。在第二个目标中，我们建议研究αKap函数增益的影响 亚核缺陷小鼠对受损NMJ的成熟与维持 抗肌营养不良蛋白糖蛋白复合体(α-合成人营养素和α-抗肌营养不良蛋白)。在 第三个目标，我们建议研究DGC亚单位之间的分子机制联系。 复合体/AChRKAP/脱泛素化酶USP9X及其在小鼠体内的稳定性 缺乏α-Syntroin/α-dystrobrevin和USP9X。这些研究的结果将是 与许多神经肌肉疾病有关，这些疾病的AChRs的数量和密度 妥协了。

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.