PT - JOURNAL ARTICLE AU - Huda, Saif AU - Cao, Michelangelo AU - De Rosa, Anna AU - Woodhall, Mark AU - Rodriguez Cruz, Pedro M. AU - Cossins, Judith AU - Maestri, Michelangelo AU - Ricciardi, Roberta AU - Evoli, Amelia AU - Beeson, David AU - Vincent, Angela TI - SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody AID - 10.1212/NXI.0000000000000645 DP - 2020 Jan 01 TA - Neurology - Neuroimmunology Neuroinflammation PG - e645 VI - 7 IP - 1 4099 - http://nn.neurology.org/content/7/1/e645.short 4100 - http://nn.neurology.org/content/7/1/e645.full SO - Neurol Neuroimmunol Neuroinflamm2020 Jan 01; 7 AB - 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.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