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Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability.

重症肌无力: 从关注乙酰胆碱受体聚集、跨突触稳态和突触稳定性的致病性观点出发。

  • 影响因子:3.97
  • DOI:10.3389/fnmol.2020.00086
  • 作者列表:"Takamori M
  • 发表时间:2020-05-28
Abstract

: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.

摘要

: 重症肌无力 (MG) 是突触后神经肌肉接头 (NMJ) 的一种疾病,烟碱乙酰胆碱 (ACh) 受体 (AChRs) 被自身抗体靶向。搜索其他致病抗原已检测到抗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,两者都引起突触前和突触后损伤。Agrin 也被怀疑是第四种病原体。在一个以麝香为中心的复杂 NMJ 组织中: (1) Wnt 非经典途径通过 Wnt-Lrp4-MuSK 富含半胱氨酸的结构域 (CRD) 蓬乱 (Dvl,支架蛋白) 信号传导作用与轴突引导形成 AChR 前模式; (2) 神经 agrin-Lrp4-MuSK (Ig1/2 结构域)信号作用在肌肉的神经支配阶段形成 rapsyn 锚定的 AChR 簇; (3) 接头蛋白 Dok-7 从 “内部” 作用于 MuSK 激活 AChR 聚集,也作用于细胞骨架,通过下游效应器 Sorbs1/2 稳定 AChR 聚集; (4) 跨突触逆行信号通过以下途径促进突触前组织:(I) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 通路; (ii) Lrp4; 和 (iii) 层粘连蛋白。突触前 Ca2 + 稳态调理 ACh 释放被自感受器如 M1-type 毒蕈碱 AChR 和 A2A 腺苷受体修饰。突触后结构通过以下方式稳定 :( i) 层粘连蛋白网络,包括肌肉来源的 agrin; (ii) 细胞外基质蛋白 (包括与 MuSK Ig1 结构域和 CRD 相关的胶原 Q/perlecan 和 biglycan); 和 (iii) dystrophin 相关糖蛋白复合物。对抗体识别的麝香外域 (Ig1/2 结构域和 CRD) 的研究表明,麝香抗体由于与多个功能结构域结合而具有病理异质性。聚焦其中一个基质蛋白,biglycan,其功能类似于胶原 Q,我们的抗体检测显示 MG 患者的阴性结果。然而,由于 biglycan 与 MuSK Ig1 结构域和 CRD 的连接,针对 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 的致病性多样性。

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发表时间:2020-01-16
DOI:10.1088/1741-2552/ab6cb6
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