TY - JOUR
T1 - Anti-MuSK autoantibodies block binding of collagen Q to MuSK
AU - Kawakami, Y.
AU - Ito, M.
AU - Hirayama, M.
AU - Sahashi, K.
AU - Ohkawara, B.
AU - Masuda, A.
AU - Nishida, H.
AU - Mabuchi, N.
AU - Engel, A. G.
AU - Ohno, K.
N1 - Funding Information:
Dr. Kawakami, Dr. Ito, Dr. Hirayama, Dr. Sahashi, Dr. Ohkawara, Dr. Masuda, Dr. Nishida, and Dr. Mabuchi report no disclosures. Dr. Engel serves as an Associate Editor of Neurology®; receives publishing royalties for Myology 3rd ed. (McGraw-Hill, 2004); and has received research support from the NIH and the Muscular Dystrophy Association. Dr. Ohno has received Grants-in-Aids from the Japan Society for the Promotion of Science, the Ministry of Health, Labour and Welfare, and the Japan Science and Technology Agency.
Funding Information:
Study funding: Supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; a Grant-in-Aid from the Ministry of Health, Labor, and Welfare of Japan; a research grant from the National Institute of Neurological Disorders and Stroke (NS6277); and a research grant from the Muscular Dystrophy Association.
PY - 2011/11/15
Y1 - 2011/11/15
N2 - Objective: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%-15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK-immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. Methods: We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of Colq-/- mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice. Results: The in vitro overlay assay revealed that MuSK-IgG blocks binding of ColQ to the neuromuscular junction. The in vitro plate-binding assay showed that MuSK-IgG exerts a dosedependent block of MuSK binding to ColQ by but not to LRP4. Passive transfer of MuSK-IgG to mice reduced the size and density of ColQ tõ10% of controls and had a lesser effect on the size and density of AChR and MuSK. Conclusions: As lack of ColQ compromises agrin-mediated AChR clustering in Colq-/- mice, a similar mechanism may lead to AChR deficiency in MuSK-MG patients. Our experiments also predict partial AChE deficiency in MuSK-MG patients, but AChE is not reduced in biopsied NMJs. In humans, binding of ColQ to MuSK may be dispensable for clustering ColQ, but is required for facilitating AChR clustering. Further studies will be required to elucidate the basis of this paradox.
AB - Objective: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%-15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK-immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. Methods: We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of Colq-/- mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice. Results: The in vitro overlay assay revealed that MuSK-IgG blocks binding of ColQ to the neuromuscular junction. The in vitro plate-binding assay showed that MuSK-IgG exerts a dosedependent block of MuSK binding to ColQ by but not to LRP4. Passive transfer of MuSK-IgG to mice reduced the size and density of ColQ tõ10% of controls and had a lesser effect on the size and density of AChR and MuSK. Conclusions: As lack of ColQ compromises agrin-mediated AChR clustering in Colq-/- mice, a similar mechanism may lead to AChR deficiency in MuSK-MG patients. Our experiments also predict partial AChE deficiency in MuSK-MG patients, but AChE is not reduced in biopsied NMJs. In humans, binding of ColQ to MuSK may be dispensable for clustering ColQ, but is required for facilitating AChR clustering. Further studies will be required to elucidate the basis of this paradox.
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U2 - 10.1212/WNL.0b013e318237f660
DO - 10.1212/WNL.0b013e318237f660
M3 - Article
C2 - 22013178
AN - SCOPUS:82955228943
SN - 0028-3878
VL - 77
SP - 1819
EP - 1826
JO - Neurology
JF - Neurology
IS - 20
ER -