SHP2 抑制剂可保护 AChR 免受重症肌无力 MuSK 抗体的影响。
SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody.
机构信息
From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic University, Rome, Italy.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2019 Dec 12;7(1). doi: 10.1212/NXI.0000000000000645. Print 2020 Jan.
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.
目的
确定Src 同源 2 结构域含磷酪氨酸磷酸酶 2（SHP2）抑制剂是否会增加肌肉特异性激酶（MuSK）磷酸化并克服 MuSK 抗体（Abs）的抑制作用。
方法
在具有 31 种 MuSK-重症肌无力（MG）血清和纯化的 MuSK-MG IgG4 制剂的 C2C12 肌管中，测试 SHP2 抑制剂 NSC-87877 对 MuSK 磷酸化和 AChR 聚集的影响。
结果
在不存在 MuSK-MG Abs 的情况下，NSC-87877 增加了 C2C12 肌管中 MuSK 的磷酸化和 AChR 簇的数量，并在 DOK7 过表达的 C2C12 肌管中形成自发的 AChR 簇。在存在 MuSK-MG 血清的情况下，AChR 簇如预期减少，但 NSC-87877 能够保护或恢复这些簇。两种纯化的 MuSK-MG IgG4 制剂均抑制 MuSK 磷酸化和 AChR 簇形成，在这两种情况下，均使用 NSC-87877 恢复了簇。
结论
用 NSC-87877 或其他药物刺激 agrin-LRP4-MuSK-DOK7 AChR 聚集途径，可能是 MuSK-MG 的一种新的治疗方法，并且可能潜在改善其他 NMJ 疾病，这些疾病的 AChR 数量减少或 NMJ 受损。
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