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. 2020 May 28:13:86.
doi: 10.3389/fnmol.2020.00086. eCollection 2020.

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

Masaharu Takamori  1
Affiliations

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

Masaharu Takamori. Front Mol Neurosci. .

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.

Keywords: Lrp4; MuSK; acetylcholine receptor; agrin; matrix proteins; myasthenia gravis; neuromuscular junction; wnts.

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Figures

Figure 1
Figure 1
Functional organization for synaptic transmission in neuromuscular junction (NMJ) and antibody-targets. (A) Presentation by staining of cultured rat myotube with fluorescence-labeled α-bungarotoxin and by the image analyzing using a laser cytometer, indicating acetylcholine receptor (AChR) cluster (red), a synaptic stabilizing organization including extracellular matrix proteins (gree and light blue). The image is constructed on ACAS 570 (Meridian Instruments Inc., Okemos, MI, USA) which provides a graded pseudocolor image on the computer display. (B) Schematic presentation of the post-synaptic structures. Y marks attached with numbers indicate the antibodies to recognize respective targets of the functional structures. Gray frame indicates the acetylcholine receptor (AChR) cluster formation. Pink frames indicate AChR clustering by way of two signaling pathways mediated via the muscle-specific tyrosine kinase (MuSK) 1/2 domains (green-limit in the pink MuSK ectodomain and green line with arrowhead) and MuSK cysteine-rich domain (CRD; red-limit in the pink MuSK ectodomain and red-line with arrowhead), the signals of which are mediated by Dishevelled (Dvl, adaptor protein). The low-density lipoprotein receptor-related protein 4 (Lrp4) is the receptor for agrin (partly for Wnts as described in the text). The small GTPases (shown in the pink frame of Kinases) effector PAK1 (p21-activated kinase 1) acts as a bridging molecule between the Wnt- and agrin-signaling pathways. From “inside” the muscle cell, MuSK is activated by Dok7 (downstream kinase); Dok7 recruits two adaptor protein, Crk and Crk-L (CT10 regulators of kinase) for rapsyn-anchored AChR cluster formation. The formed AChR clusters are anchored at the endplate membrane by rapsyn and immobilized by MuSK-linking heat-shock proteins (HSPs): tumorous imaginal disc 1 short form (Tid1s), HSP 70 and HSP 90β. Tid1s is required for the MuSK-Dok7 signaling during the MuSK activation. The interaction of neuregulin 1 (NRG 1) with ErbB receptor (receptor tyrosine kinase of epidermal growth factor receptor family) increases the MuSK tyrosine phosphorylation (via Erbin) and thereby modulates the MuSK-dependent AChR clustering. Caveolin 3 binds with the MuSK kinase domain and thereby driving AChR clustering. Yellow frames indicate the organizations for synaptic stability and maintenance. The synaptic stability of NMJ including AChR clusters (gray frame), MuSK (pink frame), Lrp4 (pink frame) and acetylcholinesterase (AChE) is modulated by extracellular matrix proteins (collagen Q, perlecan, biglycan, laminin-network including muscle agrin and laminins and dystroglycan) worked in cooperation with the cytoskeleton. The interaction of NRG 1 (neuregulin 1) with ErbB receptor (pink frames) contributes to the cytoskeletal organization through α-dystrobrevin phosphorylation on one hand (yellow frame) and the MuSK activation via Erbin on the other hand (pink frame). The downstream effector of Dok7-recruited Crk-L (Sorbs1/2) acts on the cytoskeleton for synaptic stability. Collagen Q-Perlecan and Biglycan act on Dystroglycans in cooperation with cytoskeleton for synaptic stability on one hand (yellow frame) and implicate in AChR cluster formation via their interaction with pink-MuSK ectodomains (Ig1 shown by green limit with a green line and CRD shown by red limit with red line) on the other hand. The former is cooperated by linking to dystrophin/utrophin-associated protein complex; the latter is cooperated by linking with rapsyn to firmly anchor AChR clusters at the post-synaptic membrane. Cortactin (yellow frame) has the function of phosphorylation-dependent signaling downstream from Agrin/Lrp4/MuSK (pink frame) in promoting actin polymerization and also stabilizing AChR clusters at the postsynaptic membrane. Coronin 6 is the actin-binding protein contributive to synaptic stability. Targets recognized by antibodies: Y1, Acetylcholine receptor (AChR); Y2, Muscle-specific tyrosine kinase (MuSK) 1/2 domains; Y3, MuSK cysteine-rich domain (CRD); Y4, Low-density lipoprotein receptor-related protein 4 (Lrp4); Y5, neural Agrin; Y6, Collagen Q; Y7, Cortactin.
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