Abstract
Objective To determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).
Methods The effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.
Results In the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877.
Conclusions Stimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.
Glossary
- AChR=
- acetylcholine receptor;
- CBA=
- cell-based assay;
- DOK7=
- downstream of kinase 7;
- FACS=
- fluorescence-activated cell sorting;
- KO=
- knockout;
- LRP4=
- low-density lipoprotein receptor-related protein 4;
- MG=
- myasthenia gravis;
- MuSK=
- muscle-specific kinase;
- NMJ=
- neuromuscular junction;
- SHP2=
- Src homology 2 domain-containing phosphotyrosine phosphatase 2;
- SK=
- specific kinase
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* Joint first authors—these authors contributed equally to the manuscript.
The Article Processing Charge was funded by Medical Research Council/Oxford University.
Editorial, page e646
- Received August 15, 2019.
- Accepted in final form October 8, 2019.
- Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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