Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre- and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. In a complex NMJ organization centering on MuSK: (1) the Wnt non-canonical pathway through the Wnt-Lrp4-MuSK cysteine-rich domain (CRD)-Dishevelled (Dvl, scaffold protein) signaling acts to form AChR prepatterning with axonal guidance; (2) the neural agrin-Lrp4-MuSK (Ig1/2 domains) signaling acts to form rapsyn-anchored AChR clusters at the innervated stage of muscle; (3) adaptor protein Dok-7 acts on MuSK activation for AChR clustering from “inside” and also on cytoskeleton to stabilize AChR clusters by the downstream effector Sorbs1/2; (4) the trans-synaptic retrograde signaling contributes to the presynaptic organization via: (i) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 pathway; (ii) Lrp4; and (iii) laminins. The presynaptic Ca²⁺ homeostasis conditioning ACh release is modified by autoreceptors such as M1-type muscarinic AChR and A2A adenosine receptors. The post-synaptic structure is stabilized by: (i) laminin-network including the muscle-derived agrin; (ii) the extracellular matrix proteins (including collagen Q/perlecan and biglycan which link to MuSK Ig1 domain and CRD); and (iii) the dystrophin-associated glycoprotein complex. The study on MuSK ectodomains (Ig1/2 domains and CRD) recognized by antibodies suggested that the MuSK antibodies were pathologically heterogeneous due to their binding to multiple functional domains. Focussing one of the matrix proteins, biglycan which functions in the manner similar to collagen Q, our antibody assay showed the negative result in MG patients. However, the synaptic stability may be impaired by antibodies against MuSK ectodomains because of the linkage of biglycan with MuSK Ig1 domain and CRD. The pathogenic diversity of MG is discussed based on NMJ signaling molecules.

重症肌无力（MG）是突触后神经肌肉接头（NMJ）的疾病，其中烟碱乙酰胆碱（ACh）受体（AChRs）被自身抗体靶向。寻找其他致病性抗原已检测到针对肌肉特异性酪氨酸激酶（MuSK）和低密度脂蛋白相关蛋白4（Lrp4）的抗体，均引起突触前和突触后损伤。Agrin也被怀疑是第四病原体。在一个以MuSK为中心的复杂NMJ组织中：（1）通过Wnt-Lrp4-MuSK富含半胱氨酸结构域（CRD）-杂散（Dvl，支架蛋白）的Wnt非经典途径通过轴突引导形成AChR。（2）神经agrin-Lrp4-MuSK（Ig1 / 2结构域）信号传导在肌肉神经支配阶段形成rapsyn锚定的AChR簇。（3）衔接蛋白Dok-7通过“内在”作用于ASK簇的MuSK激活，并通过下游效应器Sorbs1 / 2稳定细胞骨架，稳定AChR簇。（4）突触后逆行信号有助于突触前组织通过：（i）Wnt-MuSKCRD-Dvl-βcatenin-Slit 2途径；（ii）Lrp4；（iii）层粘连蛋白。突触前Ca ²⁺通过自身受体（例如M1型毒蕈碱AChR和A2A腺苷受体）可调节ACh的体内稳态释放。突触后结构可通过以下方式稳定：（i）层粘连蛋白网络，包括肌肉衍生的凝集素；（ii）细胞外基质蛋白（包括与MuSK Ig1结构域和CRD连接的Q / perlecan胶原蛋白和biglycan胶原蛋白）；（iii）肌营养不良蛋白相关糖蛋白复合物。对抗体识别的MuSK胞外域（Ig1 / 2域和CRD）的研究表明，由于MuSK抗体与多个功能域的结合，它们在病理上是异质的。我们的抗体测定法聚焦于一种基质蛋白，双糖链蛋白聚糖，其功能类似于胶原蛋白Q，在MG患者中显示阴性结果。然而，由于双链蛋白聚糖与MuSK Ig1结构域和CRD的连接，抗MuSK胞外域的抗体可能会损害突触稳定性。基于NMJ信号分子讨论了MG的致病多样性。