TY - JOUR
T1 - SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
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 Stampanoni-B, Amelia
AU - Beeson, David
AU - Vincent, Angela
PY - 2020
Y1 - 2020
N2 - 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.
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.
KW - myasthenia gravis
KW - myasthenia gravis
UR - http://hdl.handle.net/10807/148570
U2 - 10.1212/NXI.0000000000000645
DO - 10.1212/NXI.0000000000000645
M3 - Article
SN - 2332-7812
VL - 7
SP - 1
EP - 11
JO - NEUROLOGY® NEUROIMMUNOLOGY & NEUROINFLAMMATION
JF - NEUROLOGY® NEUROIMMUNOLOGY & NEUROINFLAMMATION
ER -