Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis
| Autor: | Peter M. Frederik, Marc H. De Baets, Frank Spaans, Henk Veldman, John H. J. Wokke, Angela Vincent, Hans Duimel, Mario Losen, Maurice H. W. Stassen, Pilar Martinez-Martinez, Barbie M. Machiels |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
animal structures Neuromuscular transmission Neuromuscular Junction Radioimmunoassay Action Potentials Fluorescent Antibody Technique Muscle Proteins Biology Synaptic Transmission Neuromuscular junction Tibialis anterior muscle Downregulation and upregulation Postsynaptic potential Internal medicine medicine Animals Receptors Cholinergic Muscle Skeletal Acetylcholine receptor Microscopy Confocal Electromyography medicine.disease Immunohistochemistry Myasthenia gravis Myasthenia Gravis Autoimmune Experimental Rats Up-Regulation Microscopy Electron Endocrinology medicine.anatomical_structure Rats Inbred Lew Acute Disease Cholinergic Female Neurology (clinical) |
| Zdroj: | Brain : a journal of neurology. 128(Pt 10) |
| ISSN: | 1460-2156 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|