Journal Article

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

Mario Losen, Maurice H. W. Stassen, Pilar Martínez-Martínez, Barbie M. Machiels, Hans Duimel, Peter Frederik, Henk Veldman, John H. J. Wokke, Frank Spaans, Angela Vincent and Marc H. De Baets

in Brain

Published on behalf of The Guarantors of Brain

Volume 128, issue 10, pages 2327-2337
Published in print October 2005 | ISSN: 0006-8950
Published online September 2005 | e-ISSN: 1460-2156 | DOI:
Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis

Show Summary Details


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; α-BT = α-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

Journal Article.  6730 words.  Illustrated.

Subjects: Neurology ; Neuroscience

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.