Silencing rapsyn in vivo decreases acetylcholine receptors and augments sodium channels and secondary postsynaptic membrane folding

Martínez‐Martínez, Pilar; Phernambucq, Marko; Steinbusch, Laura K. M.; Schaeffer, Laurent; Berrih‐Aknin, Sonia; Duimel, Hans; Frederik, Peter M.; Molenaar, Peter; Baets, Marc H. De; Losen, Mario

doi:10.1016/j.nbd.2009.03.008

Cited by 20 publications

(24 citation statements)

References 70 publications

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“…There is a wealth of studies showing a direct correlation between the amount of rapsyn present at NMJs and the abundance or the metabolic stability of synaptic AChRs (Brockhausen et al, 2008;Gervasio et al, 2007;Gervasio and Phillips, 2005;Luo et al, 2008;Martinez-Martinez et al, 2009;Wang et al, 1999). Furthermore, mutations in the RAPSN gene are amongst the most frequent causes for myasthenic syndromes, which are characterised by activity-dependent muscle weakness (Beeson et al, 2008;Müller et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Choi

Berrera

Reischl

et al. 2012

Journal of Cell Science

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SummaryThe stabilisation of acetylcholine receptors (AChRs) at the neuromuscular junction depends on muscle activity and the cooperative action of myosin Va and protein kinase A (PKA) type I. To execute its function, PKA has to be present in a subsynaptic microdomain where it is enriched by anchoring proteins. Here, we show that the AChR-associated protein, rapsyn, interacts with PKA type I in C2C12 and T-REx293 cells as well as in live mouse muscle beneath the neuromuscular junction. Molecular modelling, immunoprecipitation and bimolecular fluorescence complementation approaches identify an a-helical stretch of rapsyn to be crucial for binding to the dimerisation and docking domain of PKA type I. When expressed in live mouse muscle, a peptide encompassing the rapsyn a-helical sequence efficiently delocalises PKA type I from the neuromuscular junction. The same peptide, as well as a rapsyn construct lacking the a-helical domain, induces severe alteration of acetylcholine receptor turnover as well as fragmentation of synapses. This shows that rapsyn anchors PKA type I in close proximity to the postsynaptic membrane and suggests that this function is essential for synapse maintenance.

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Section: Discussionmentioning

confidence: 99%

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Choi

Berrera

Reischl

et al. 2012

Journal of Cell Science

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“…For each experimental group, 10–15 muscle sections were analyzed as previously described [61], [62]. Muscle sections were fixed in cold acetone for 10 min and washed them in PBS three times for 5 min.…”

Section: Methodsmentioning

confidence: 99%

Prophylactic Effect of Probiotics on the Development of Experimental Autoimmune Myasthenia Gravis

et al. 2012

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Probiotics are live bacteria that confer health benefits to the host physiology. Although protective role of probiotics have been reported in diverse diseases, no information is available whether probiotics can modulate neuromuscular immune disorders. We have recently demonstrated that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental disorders in mice model. In this study we further investigated whether IRT5 probiotics could modulate the progression of experimental autoimmune myasthenia gravis (EAMG). Myasthenia gravis (MG) is a T cell dependent antibody mediated autoimmune disorder in which acetylcholine receptor (AChR) at the neuromuscular junction is the major auto-antigen. Oral administration of IRT5 probiotics significantly reduced clinical symptoms of EAMG such as weight loss, body trembling and grip strength. Prophylactic effect of IRT5 probiotics on EMAG is mediated by down-regulation of effector function of AChR-reactive T cells and B cells. Administration of IRT5 probiotics decreased AChR-reactive lymphocyte proliferation, anti-AChR reactive IgG levels and inflammatory cytokine levels such as IFN-γ, TNF-α, IL-6 and IL-17. Down-regulation of inflammatory mediators in AChR-reactive lymphocytes by IRT5 probiotics is mediated by the generation of regulatory dendritic cells (rDCs) that express increased levels of IL-10, TGF-β, arginase 1 and aldh1a2. Furthermore, DCs isolated from IRT5 probiotics-fed group effectively converted CD4+ T cells into CD4+Foxp3+ regulatory T cells compared with control DCs. Our data suggest that IRT5 probiotics could be applicable to modulate antibody mediated autoimmune diseases including myasthenia gravis.

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“…The resistance against curare was used as an indirect, albeit nonlinear, measure for the safety factor of neuromuscular transmission and thus for the performance of neuromuscular transmission (33,34).…”

Section: Electromyographymentioning

confidence: 99%

“…At least five endplate regions were photographed from each muscle. Quantitative morphometry of the folding index (length of postsynaptic membrane/length of presynaptic membrane) was performed as previously described (34,35). For the analysis, the following number of animals was used per group: control saline (n = 3); EAMG saline (n = 4); EAMG 4w-Bz (n = 4); EAMG 8w-Bz (n = 4).…”

Section: Em Of Muscle Tissuementioning

confidence: 99%

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez

Vrolix

Martínez‐Martínez

et al. 2011

The Journal of Immunology

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Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases.

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Silencing rapsyn in vivo decreases acetylcholine receptors and augments sodium channels and secondary postsynaptic membrane folding

Cited by 20 publications

References 70 publications

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Prophylactic Effect of Probiotics on the Development of Experimental Autoimmune Myasthenia Gravis

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

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