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