RT Journal Article
SR Electronic
T1 SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e645
DO 10.1212/NXI.0000000000000645
VO 7
IS 1
A1 Saif Huda
A1 Michelangelo Cao
A1 Anna De Rosa
A1 Mark Woodhall
A1 Pedro M. Rodriguez Cruz
A1 Judith Cossins
A1 Michelangelo Maestri
A1 Roberta Ricciardi
A1 Amelia Evoli
A1 David Beeson
A1 Angela Vincent
YR 2020
UL http://nn.neurology.org/content/7/1/e645.abstract
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