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.

Huda, S., Cao, M., De Rosa, A., Woodhall, M., Rodriguez Cruz, P. M., Cossins, J., Maestri, M., Ricciardi, R., Evoli, A., Beeson, D., Vincent, A., SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody, <<NEUROLOGY® NEUROIMMUNOLOGY & NEUROINFLAMMATION>>, 2020; 7 (1): 1-11. [doi:10.1212/NXI.0000000000000645] [http://hdl.handle.net/10807/148570]

SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody

Evoli, Amelia
;
2020

Abstract

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.
Inglese
Huda, S., Cao, M., De Rosa, A., Woodhall, M., Rodriguez Cruz, P. M., Cossins, J., Maestri, M., Ricciardi, R., Evoli, A., Beeson, D., Vincent, A., SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody, <<NEUROLOGY® NEUROIMMUNOLOGY & NEUROINFLAMMATION>>, 2020; 7 (1): 1-11. [doi:10.1212/NXI.0000000000000645] [http://hdl.handle.net/10807/148570]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/148570
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 8
social impact