Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling

Kenji Otsuka; Mikako Ito; Bisei Ohkawara; Akio Masuda; Yu Kawakami; Ko Sahashi; Hiroshi Nishida; Naoki Mabuchi; Akemi Takano; Andrew G. Engel; Kinji Ohno

doi:10.1038/srep13928

Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling

Kenji Otsuka, Mikako Ito, Bisei Ohkawara, Akio Masuda, Yu Kawakami, Ko Sahashi, Hiroshi Nishida, Naoki Mabuchi, Akemi Takano, Andrew G. Engel, Kinji Ohno

Neurology

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

MuSK antibody-positive myasthenia gravis (MuSK-MG) accounts for 5 to 15% of autoimmune MG. MuSK and LRP4 are coreceptors for agrin in the signaling pathway that causes clustering of acetylcholine receptor (AChR). MuSK also anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. We previously reported that anti-MuSK antibodies (MuSK-IgG) block binding of ColQ to MuSK and cause partial endplate AChE deficiency in mice. We here analyzed the physiological significance of binding of ColQ to MuSK and block of this binding by MuSK-IgG. In vitro plate-binding assay showed that MuSK-IgG blocked MuSK-LRP4 interaction in the presence of agrin. Passive transfer of MuSK-IgG to Colq-knockout mice attenuated AChR clustering, indicating that lack of ColQ is not the key event causing defective clustering of AChR in MuSK-MG. In three MuSK-MG patients, the MuSK antibodies recognized the first and fourth immunoglobulin-like domains (Ig1 and Ig4) of MuSK. In two other MuSK-MG patients, they recognized only the Ig4 domain. LRP4 and ColQ also bound to the Ig1 and Ig4 domains of MuSK. Unexpectedly, the AChE/ColQ complex blocked MuSK-LRP4 interaction and suppressed agrin/LRP4/MuSK signaling. Quantitative analysis showed that MuSK-IgG suppressed agrin/LRP4/MuSK signaling to a greater extent than ColQ.

Original language	English (US)
Article number	13928
Journal	Scientific reports
Volume	5
DOIs	https://doi.org/10.1038/srep13928
State	Published - Sep 10 2015

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@article{ee0e5f052e0f4ce083f8923ad223eb07,

title = "Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling",

abstract = "MuSK antibody-positive myasthenia gravis (MuSK-MG) accounts for 5 to 15% of autoimmune MG. MuSK and LRP4 are coreceptors for agrin in the signaling pathway that causes clustering of acetylcholine receptor (AChR). MuSK also anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. We previously reported that anti-MuSK antibodies (MuSK-IgG) block binding of ColQ to MuSK and cause partial endplate AChE deficiency in mice. We here analyzed the physiological significance of binding of ColQ to MuSK and block of this binding by MuSK-IgG. In vitro plate-binding assay showed that MuSK-IgG blocked MuSK-LRP4 interaction in the presence of agrin. Passive transfer of MuSK-IgG to Colq-knockout mice attenuated AChR clustering, indicating that lack of ColQ is not the key event causing defective clustering of AChR in MuSK-MG. In three MuSK-MG patients, the MuSK antibodies recognized the first and fourth immunoglobulin-like domains (Ig1 and Ig4) of MuSK. In two other MuSK-MG patients, they recognized only the Ig4 domain. LRP4 and ColQ also bound to the Ig1 and Ig4 domains of MuSK. Unexpectedly, the AChE/ColQ complex blocked MuSK-LRP4 interaction and suppressed agrin/LRP4/MuSK signaling. Quantitative analysis showed that MuSK-IgG suppressed agrin/LRP4/MuSK signaling to a greater extent than ColQ.",

author = "Kenji Otsuka and Mikako Ito and Bisei Ohkawara and Akio Masuda and Yu Kawakami and Ko Sahashi and Hiroshi Nishida and Naoki Mabuchi and Akemi Takano and Engel, {Andrew G.} and Kinji Ohno",

note = "Funding Information: We are also grateful to Dr. Eric Krejci at INSERM for providing Colq−/− mice. This study was supported by Grants-in-Aid from the MEXT and MHLW of Japan.",

year = "2015",

month = sep,

day = "10",

doi = "10.1038/srep13928",

language = "English (US)",

volume = "5",

journal = "Scientific reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling

AU - Otsuka, Kenji

AU - Ito, Mikako

AU - Ohkawara, Bisei

AU - Masuda, Akio

AU - Kawakami, Yu

AU - Sahashi, Ko

AU - Nishida, Hiroshi

AU - Mabuchi, Naoki

AU - Takano, Akemi

AU - Engel, Andrew G.

AU - Ohno, Kinji

N1 - Funding Information: We are also grateful to Dr. Eric Krejci at INSERM for providing Colq−/− mice. This study was supported by Grants-in-Aid from the MEXT and MHLW of Japan.

PY - 2015/9/10

Y1 - 2015/9/10

N2 - MuSK antibody-positive myasthenia gravis (MuSK-MG) accounts for 5 to 15% of autoimmune MG. MuSK and LRP4 are coreceptors for agrin in the signaling pathway that causes clustering of acetylcholine receptor (AChR). MuSK also anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. We previously reported that anti-MuSK antibodies (MuSK-IgG) block binding of ColQ to MuSK and cause partial endplate AChE deficiency in mice. We here analyzed the physiological significance of binding of ColQ to MuSK and block of this binding by MuSK-IgG. In vitro plate-binding assay showed that MuSK-IgG blocked MuSK-LRP4 interaction in the presence of agrin. Passive transfer of MuSK-IgG to Colq-knockout mice attenuated AChR clustering, indicating that lack of ColQ is not the key event causing defective clustering of AChR in MuSK-MG. In three MuSK-MG patients, the MuSK antibodies recognized the first and fourth immunoglobulin-like domains (Ig1 and Ig4) of MuSK. In two other MuSK-MG patients, they recognized only the Ig4 domain. LRP4 and ColQ also bound to the Ig1 and Ig4 domains of MuSK. Unexpectedly, the AChE/ColQ complex blocked MuSK-LRP4 interaction and suppressed agrin/LRP4/MuSK signaling. Quantitative analysis showed that MuSK-IgG suppressed agrin/LRP4/MuSK signaling to a greater extent than ColQ.

AB - MuSK antibody-positive myasthenia gravis (MuSK-MG) accounts for 5 to 15% of autoimmune MG. MuSK and LRP4 are coreceptors for agrin in the signaling pathway that causes clustering of acetylcholine receptor (AChR). MuSK also anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. We previously reported that anti-MuSK antibodies (MuSK-IgG) block binding of ColQ to MuSK and cause partial endplate AChE deficiency in mice. We here analyzed the physiological significance of binding of ColQ to MuSK and block of this binding by MuSK-IgG. In vitro plate-binding assay showed that MuSK-IgG blocked MuSK-LRP4 interaction in the presence of agrin. Passive transfer of MuSK-IgG to Colq-knockout mice attenuated AChR clustering, indicating that lack of ColQ is not the key event causing defective clustering of AChR in MuSK-MG. In three MuSK-MG patients, the MuSK antibodies recognized the first and fourth immunoglobulin-like domains (Ig1 and Ig4) of MuSK. In two other MuSK-MG patients, they recognized only the Ig4 domain. LRP4 and ColQ also bound to the Ig1 and Ig4 domains of MuSK. Unexpectedly, the AChE/ColQ complex blocked MuSK-LRP4 interaction and suppressed agrin/LRP4/MuSK signaling. Quantitative analysis showed that MuSK-IgG suppressed agrin/LRP4/MuSK signaling to a greater extent than ColQ.

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U2 - 10.1038/srep13928

DO - 10.1038/srep13928

M3 - Article

C2 - 26355076

AN - SCOPUS:84941299752

SN - 2045-2322

VL - 5

JO - Scientific reports

JF - Scientific reports

M1 - 13928

ER -

Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling

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