title: Silencing of Dok-7 in Adult Rat Muscle Increases Susceptibility to Passive Transfer Myasthenia Gravis.
abstract: Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies that target proteins at the neuromuscular junction, primarily the acetylcholine receptor (AChR) and the muscle-specific kinase. Because downstream of kinase 7 (Dok-7) is essential for the full activation of muscle-specific kinase and consequently for dense clustering of AChRs, we hypothesized that reduced levels of Dok-7 increase the susceptibility to passive transfer MG. To test this hypothesis, Dok-7 expression was reduced by transfecting shRNA-coding plasmids into the tibialis anterior muscle of adult rats by in vivo electroporation. Subclinical MG was subsequently induced with a low dose of anti-AChR monoclonal antibody 35. Neuromuscular transmission was significantly impaired in Dok-7-siRNA-electroporated legs compared with the contralateral control legs, which correlated with a reduction of AChR protein levels at the neuromuscular junction (approximately 25%) in Dok-7-siRNA-electroporated muscles, compared with contralateral control muscles. These results suggest that a reduced expression of Dok-7 may play a role in the susceptibility to passive transfer MG, by rendering AChR clusters less resistant to the autoantibody attack.
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address: alegomez@stanford.edu.
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Gomez
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: Jo A A
authors.initials: JA
authors.lastname: Stevens
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: Marina
authors.initials: M
authors.lastname: Mané-Damas
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Molenaar
authors.affiliation: Electron Microscopy Unit, Department of Molecular Cell Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Duimel
authors.affiliation: Electron Microscopy Unit, Department of Molecular Cell Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Judith
authors.initials: J
authors.lastname: Cossins
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Beeson
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: Marc H
authors.initials: MH
authors.lastname: De Baets
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: Losen
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address: p.martinez@maastrichtuniversity.nl.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martinez-Martinez
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000276:immunology / Q000503:physiopathology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000276:immunology / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D001323:Autoantibodies; C000623253:Dok7 protein, rat; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases