Acute severe animal model of anti-muscle-specific kinase myasthenia: Combined postsynaptic and presynaptic changes

David P Richman, Kayoko Nishi, Stuart W. Morell, Jolene Mi Chang, Michael J Ferns, Robert L. Wollmann, Ricardo A Maselli, Joachim Schnier, Mark A. Agius

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Objectives: To determine the pathogenesis of anti- muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and Participants: Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy. Results: Animals immunized with 100 ìg of MuSK 60 developed severe progressive weakness starting at day 16, with 100% mortality by day 27. The weakness was associated with high MuSK antibody titers, weight loss, axial muscle wasting, and decrementing compound muscle action potentials. Light and electron microscopy demonstrated fragmented NMJs with varying degrees of postsynaptic muscle end plate destruction along with abnormal nerve terminals, lack of registration between end plates and nerve terminals, local axon sprouting, and extrajunctional dispersion of cholinesterase activity. Conclusions: These findings support the role of MuSK antibodies in the human disease, demonstrate the role of MuSK not only in the development of the NMJ but also in the maintenance of the mature synapse, and demonstrate involvement of this disease in both presynaptic and postsynaptic components of the NMJ.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalArchives of Neurology
Volume69
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Phosphotransferases
Animal Models
Muscles
Neuromuscular Junction
Antibodies
Nerve
Animal Model
Electron Microscopy
Animals
Median Nerve
Myasthenia Gravis
Cholinesterases
Muscle Weakness
Presynaptic Terminals
Cholinergic Receptors
Synapses
Action Potentials
Weight Loss
Maintenance
Light

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Acute severe animal model of anti-muscle-specific kinase myasthenia : Combined postsynaptic and presynaptic changes. / Richman, David P; Nishi, Kayoko; Morell, Stuart W.; Mi Chang, Jolene; Ferns, Michael J; Wollmann, Robert L.; Maselli, Ricardo A; Schnier, Joachim; Agius, Mark A.

In: Archives of Neurology, Vol. 69, No. 4, 04.2012, p. 453-460.

Research output: Contribution to journalArticle

Richman, David P ; Nishi, Kayoko ; Morell, Stuart W. ; Mi Chang, Jolene ; Ferns, Michael J ; Wollmann, Robert L. ; Maselli, Ricardo A ; Schnier, Joachim ; Agius, Mark A. / Acute severe animal model of anti-muscle-specific kinase myasthenia : Combined postsynaptic and presynaptic changes. In: Archives of Neurology. 2012 ; Vol. 69, No. 4. pp. 453-460.
@article{6e9283a054404093bcb1630a75e8772c,
title = "Acute severe animal model of anti-muscle-specific kinase myasthenia: Combined postsynaptic and presynaptic changes",
abstract = "Objectives: To determine the pathogenesis of anti- muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and Participants: Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy. Results: Animals immunized with 100 {\`i}g of MuSK 60 developed severe progressive weakness starting at day 16, with 100{\%} mortality by day 27. The weakness was associated with high MuSK antibody titers, weight loss, axial muscle wasting, and decrementing compound muscle action potentials. Light and electron microscopy demonstrated fragmented NMJs with varying degrees of postsynaptic muscle end plate destruction along with abnormal nerve terminals, lack of registration between end plates and nerve terminals, local axon sprouting, and extrajunctional dispersion of cholinesterase activity. Conclusions: These findings support the role of MuSK antibodies in the human disease, demonstrate the role of MuSK not only in the development of the NMJ but also in the maintenance of the mature synapse, and demonstrate involvement of this disease in both presynaptic and postsynaptic components of the NMJ.",
author = "Richman, {David P} and Kayoko Nishi and Morell, {Stuart W.} and {Mi Chang}, Jolene and Ferns, {Michael J} and Wollmann, {Robert L.} and Maselli, {Ricardo A} and Joachim Schnier and Agius, {Mark A.}",
year = "2012",
month = "4",
doi = "10.1001/archneurol.2011.2200",
language = "English (US)",
volume = "69",
pages = "453--460",
journal = "Archives of Neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "4",

}

TY - JOUR

T1 - Acute severe animal model of anti-muscle-specific kinase myasthenia

T2 - Combined postsynaptic and presynaptic changes

AU - Richman, David P

AU - Nishi, Kayoko

AU - Morell, Stuart W.

AU - Mi Chang, Jolene

AU - Ferns, Michael J

AU - Wollmann, Robert L.

AU - Maselli, Ricardo A

AU - Schnier, Joachim

AU - Agius, Mark A.

PY - 2012/4

Y1 - 2012/4

N2 - Objectives: To determine the pathogenesis of anti- muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and Participants: Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy. Results: Animals immunized with 100 ìg of MuSK 60 developed severe progressive weakness starting at day 16, with 100% mortality by day 27. The weakness was associated with high MuSK antibody titers, weight loss, axial muscle wasting, and decrementing compound muscle action potentials. Light and electron microscopy demonstrated fragmented NMJs with varying degrees of postsynaptic muscle end plate destruction along with abnormal nerve terminals, lack of registration between end plates and nerve terminals, local axon sprouting, and extrajunctional dispersion of cholinesterase activity. Conclusions: These findings support the role of MuSK antibodies in the human disease, demonstrate the role of MuSK not only in the development of the NMJ but also in the maintenance of the mature synapse, and demonstrate involvement of this disease in both presynaptic and postsynaptic components of the NMJ.

AB - Objectives: To determine the pathogenesis of anti- muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and Participants: Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy. Results: Animals immunized with 100 ìg of MuSK 60 developed severe progressive weakness starting at day 16, with 100% mortality by day 27. The weakness was associated with high MuSK antibody titers, weight loss, axial muscle wasting, and decrementing compound muscle action potentials. Light and electron microscopy demonstrated fragmented NMJs with varying degrees of postsynaptic muscle end plate destruction along with abnormal nerve terminals, lack of registration between end plates and nerve terminals, local axon sprouting, and extrajunctional dispersion of cholinesterase activity. Conclusions: These findings support the role of MuSK antibodies in the human disease, demonstrate the role of MuSK not only in the development of the NMJ but also in the maintenance of the mature synapse, and demonstrate involvement of this disease in both presynaptic and postsynaptic components of the NMJ.

UR - http://www.scopus.com/inward/record.url?scp=84859978028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859978028&partnerID=8YFLogxK

U2 - 10.1001/archneurol.2011.2200

DO - 10.1001/archneurol.2011.2200

M3 - Article

C2 - 22158720

AN - SCOPUS:84859978028

VL - 69

SP - 453

EP - 460

JO - Archives of Neurology

JF - Archives of Neurology

SN - 0003-9942

IS - 4

ER -