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Brain Advance Access published online on September 8, 2005
Brain, doi:10.1093/brain/awh612
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received March 22, 2005
Revised July 14, 2005
Accepted July 18, 2005

Article

Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis

Mario Losen 1, Maurice H. W. Stassen 2, Pilar Martínez-Martínez 1, Barbie M. Machiels 1, Hans Duimel 3, Peter Frederik 3, Henk Veldman 4, John H. J. Wokke 4, Frank Spaans 5, Angela Vincent 6, and Marc H. De Baets 7*

1 Department of Neurology, Research Institute Brain and Behaviour, University of Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON), Maastricht University Hospital, Maastricht, The Netherlands
2 Department of Neurology, Research Institute Brain and Behaviour, University of Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON), Maastricht University Hospital, Maastricht, The Netherlands; Present address: Maurice H. W. Stassen, Department of Molecular Cell Biology, University of Utrecht, Utrecht, The Netherlands
3 EM Unit, Department of Pathology, University of Maastricht, The Netherlands
4 Department of Neurology, Rudolf Magnus Institute of Neurosciences, University of Utrecht, Utrecht, The Netherlands
5 Department of Clinical Neurophysiology, Maastricht University Hospital, Maastricht, The Netherlands
6 Neurosciences Group, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Oxford, UK
7 Department of Neurology, Research Institute Brain and Behaviour, University of Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON), Maastricht University Hospital, Maastricht, The Netherlands; Department of Neurology, Maastricht University Hospital, Maastricht, The Netherlands

* To whom correspondence should be addressed.
Marc H. De Baets, E-mail: mdba{at}sneu.azm.nl


  Abstract

Myasthenia gravis is usually caused by autoantibodies to the acetylcholine receptor (AChR). The AChR is clustered and anchored in the postsynaptic membrane of the neuromuscular junction (NMJ) by a cytoplasmic protein called rapsyn. We previously showed that resistance to experimental autoimmune myasthenia gravis (EAMG) in aged rats correlates with increased rapsyn concentration at the NMJ. It is possible, therefore, that endogenous rapsyn expression may be an important determinant of AChR loss and neuromuscular transmission failure in the human disease, and that upregulation of rapsyn expression could be used therapeutically. To examine first a potential therapeutic application of rapsyn upregulation, we induced acute EAMG in young rats by passive transfer of AChR antibody, mAb 35, and used in vivo electroporation to over-express rapsyn unilaterally in one tibialis anterior. We looked at the compound muscle action potentials (CMAPs) in the tibialis anterior, at rapsyn and AChR expression by quantitative radioimmunoassay and immunofluorescence, and at the morphology of the NMJs, comparing the electroporated and untreated muscles, as well as the control and EAMG rats. In control rats, transfected muscle fibres had extrasynaptic rapsyn aggregates, as well as slightly increased rapsyn and AChR concentrations at the NMJ. In EAMG rats, despite deposits of the membrane attack complex, the rapsyn-overexpressing muscles showed no decrement in the CMAPs, no loss of AChR, and the majority had normal postsynaptic folds, whereas endplates of untreated muscles showed typical AChR loss and morphological damage. These data suggest not only that increasing rapsyn expression could be a potential treatment for selected muscles of myasthenia gravis patients, but also lend support to the hypothesis that individual differences in innate rapsyn expression could be a factor in determining disease severity.

Keywords: rapsyn; experimental autoimmune myasthenia gravis (EAMG); gene therapy; electropermeabilization; in vivo electroporation.
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