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Brain Advance Access originally published online on September 8, 2005
Brain 2005 128(10):2327-2337; 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

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

Mario Losen1,3, Maurice H. W. Stassen1,3, Pilar Martínez-Martínez1,3, Barbie M. Machiels1,3, Hans Duimel2, Peter Frederik2, Henk Veldman6, John H. J. Wokke6, Frank Spaans4, Angela Vincent7 and Marc H. De Baets1,3,5

1 Department of Neurology, Research Institute Brain and Behaviour, 2 EM Unit, Department of Pathology, University of Maastricht, The Netherlands, 3 European Graduate School of Neuroscience (EURON), and Departments of 4 Clinical Neurophysiology and 5 Neurology, Maastricht University Hospital, Maastricht, 6 Department of Neurology, Rudolf Magnus Institute of Neurosciences, University of Utrecht, Utrecht, The Netherlands and 7 Neurosciences Group, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Oxford, UK

Correspondence to: Dr Marc De Baets, Department of Neurology, Maastricht University Hospital, PO Box 5800, 6202 AZ Maastricht, The Netherlands E-mail: mdba{at}sneu.azm.nl Present address: Maurice H. W. Stassen, Department of Molecular Cell Biology, University of Utrecht, Utrecht, The Netherlands

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.

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

Abbreviations: {alpha}-BT = {alpha}-bungarotoxin; AChR = acetylcholine receptor; BN rat = Brown Norway rat; CMAP = compound muscle action potential; EMG = electromyography; EAMG = experimental autoimmune myasthenia gravis; mAb = monoclonal antibody; MAC = membrane attack complex; MuSK = muscle-specific kinase; NMJ = neuromuscular junction; RIA = radioimmunoassay; VAChT = vesicular acetylcholine transporter

Received March 22, 2005. Revised July 14, 2005. Accepted July 18, 2005.


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