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1
Carr, A. S. "An epidemiological study of myasthenia gravis and congenital myasthenic syndromes in Northern Ireland." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546021.
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Abdelgany, Amr. "Gene therapy for congenital myasthenic syndromes." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441062.
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Finlayson, Sarah E. "Congenital myasthenic syndromes : current diagnostic and therapeutic aspects." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:5e08ab86-8a20-48b3-86b9-683eb8b2c6e4.
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Zoltowska, Katarzyna Marta. "Novel pathogenic mechanisms of myasthenic disorders and potential therapeutic approaches." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:e817f50a-0318-4944-bf67-773af523c4c3.
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Congenital myasthenic syndrome (CMS) and myasthenia gravis (MG) are, respectively, inherited or autoimmunological disorders caused by aberrant neuromuscular transmission, which manifests as fatiguable muscle weakness. A novel subtype of CMS, resulting from mutations in GFPT1 and characterised by a limb girdle pattern of muscle weakness, has been described. The gene encodes L glutamine:D fructose-6-phosphate amidotransferase 1 (GFAT1) – a key rate limiting enzyme in the hexosamine biosynthetic pathway, providing building blocks for glycosylation of proteins and lipids. The research focused on the molecular bases of the CMS resulting from mutations in the ubiquitously expressed gene, but with symptoms largely restricted to the neuromuscular junction (NMJ). The work has established a link between the NMJ and GFPT1 CMS by demonstrating that the AChR cell surface is decreased in GFPT1 patient muscle cells and in GFPT1-silenced cell lines. The decrease is likely to be caused by reduced steady-state levels of individual AChR α, δ and ε, but not β, subunits. To optimise treatment for myasthenic disorders, a comparative in vivo trial of therapy with pyridostigmine bromide and salbutamol sulphate, and pyridostigmine bromide alone, was conducted. Supplementation of the AChE inhibitor-based therapy with the β2-adrenergic receptor agonist had a beneficial effect. This offers promise for more effective treatments for CMS and MG affected individuals. Molecular causes of MG were also investigated. The search for novel antibody targets was conducted with the use of a designed cell-based assay for the detection of anti COLQ autoimmunoglobulins in MG patient sera. The antibodies were detected in 24 out of 418 analysed samples, but their pathogenicity has not been determined.
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Cheung, Jonathan Yu. "Pathogenic mechanisms of RAPSN mutations in congenital myasthenic syndromes." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:c343ca03-563e-4b4a-9e35-aac09bfc5ea7.
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Rapsyn is essential for clustering acetylcholine receptors (AChR) at the neuromuscular junction (NMJ). Congenital myasthenic syndrome (CMS) due to RAPSN mutations compromises neuromuscular transmission through a deficiency of AChR at the NMJ. RAPSN-CMS is autosomal recessive, and most patients harbour a common mutation p.Asn88Lys. A definitive genetic diagnosis for patients who do not carry the p.Asn88Lys allele can be challenging. In this thesis 10 novel variants in RAPSN are shown to impair AChR clustering in vitro, and are thus defined as pathogenic. The properties of RAPSN mutations p.Val45M, p.Asn88Lys, p.Arg91Leu and p.Ala153Thr were studied and were found to be diverse, though common mechanisms were found to underlie the AChR deficiency. The mutations reduce the stability of rapsyn and the stability of AChR-rapsyn clusters formed on cultured myotubes. A unique missense mutation in the AChR d-subunit encoding gene, p.Glu381Lys, phenotypically mimics RAPSN-CMS, and investigations revealed that this mutation also causes instability of the AChR clusters. Salbutamol, a medication that is believed to stabilise NMJ, has recently been found to benefit AChR deficiency patients when used in combination with pyridostigmine. However, the mode of action of salbutamol at the NMJ is undefined. A pilot study was performed to evaluate the efficacy and mechanism of salbutamol therapy in a mouse model of AChR deficiency. Methodologies were established for the analysis of the effects of salbutamol and will provide the basis for a more detailed study of its beneficial action in disorders of neuromuscular transmission.
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Issop, Yasmin. "A GFPT1 deficient mouse model of congenital myasthenic syndrome." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3902.
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Congenital myasthenic syndromes (CMS) are inherited disorders characterised by fatigable muscle weakness resulting from impaired transmission at the neuromuscular junction (NMJ). CMS occur due to mutations in genes encoding proteins responsible for maintaining the structure and function of the NMJ. Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway which yields precursors required for protein and lipid glycosylation. Mutations in GFPT1 and genes downstream of this pathway are pathogenic for CMS. One hypothesis is that hypoglycosylation of NMJ proteins results in defective neurotransmission. The aim of this study is to generate and characterise a GFPT1 deficient mouse model of CMS. One of the challenges we face is the viability of Gfpt1 knockout mice. Here we generate a novel muscle-specific GFPT1 knockout mouse model using Cre/loxP technology. We demonstrate that a deficiency of GFPT1 in muscle only, is sufficient for causing a CMS phenotype. Our model recapitulates many aspects of the phenotype observed in patients with GFPT1-related CMS. Mutant mice display early changes in the morphology of postsynaptic components of the NMJ, which are accompanied by presynaptic alterations. They later develop a myopathic phenotype and formation of tubular aggregates. We further identify proteins in skeletal muscle that are differentially regulated because of GFPT1 deficiency. Our data demonstrates a critical role for GFPT1 in the development of the NMJ, neurotransmission, and skeletal muscle integrity. The muscle-specific GFPT1 deficient mouse model allows us to investigate the implications of not only GFPT1 mutations, but may also give us an insight into the pathophysiological consequences of mutations in genes downstream of GFPT1, which also result in hypoglycosylation. This model has the potential to enhance our understanding of current drug therapies, and to drive forward the development of new compounds which can be implemented in the clinic.
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Chaouch, Amina. "The clinical and genetic characteristics of congenital myasthenic syndromes." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2748.
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Congenital myasthenic syndromes (CMS) are inherited disorders in which the safety margin of the neuromuscular transmission is compromised. The clinical hallmark of CMS is fatigable weakness. To date, nineteen genes have been implicated in causing this disorder, with most mutations located in postsynaptic proteins. Nevertheless, a great proportion of patients remains with no molecular diagnosis and cannot therefore access optimum therapy. In this thesis, each topic is summarized in one chapter that corresponds to one or part of a selected journal publication, or a book chapter. Chapter 1 is dedicated to the review of our current understanding of the different CMS subgroups based on their underlying molecular defects. Chapter 2 focuses on the methodology used to acquire the data described in the subsequent chapters. Chapter 3 reports on the mutation distribution, clinical features and genotype phenotype correlation of CMS patients referred to one of the largest CMS diagnostic centres worldwide. The phenotype genotype correlation and response to treatment in specific CMS subgroups are refined in chapters 4 and 5, including slow channel CMS and GFPT1 associated CMS respectively. Chapter 6 focuses on the selection strategy of an undiagnosed CMS cohort for whole exome sequencing and reports on the candidate variants identified. Finally, in chapter 7 and 8, detailed clinical and biological data are shown to demonstrate the pathogenicity of novel AGRN and SLC25A1 mutations identified using next generation sequencing.
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Childs, Lisbeth Ann. "The effects of myasthenic serum on skeletal muscle cells in culture." Thesis, University of Bath, 1985. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484407.
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Rat muscle cells were grown in culture for use as an experimental model in which to study the myolytic effects of myasthenic serum in vitro. Use was made of a procedure which depends upon the selective uptake of tritium-labelled carnitine by cultured myotubes, loss of which can be monitored following cytolytic damage. The studies demonstrated that heat-inactivated myasthenic serum samples caused myotube-specific lysis in a manner that was dependent on the addition of complement. The concentration and activity of the complement source was shown to be a major factor in detecting myotoxicity. Using optimised assay conditions, a myotoxicity study was carried out using a range of normal and myasthenic serum samples. In the presence of guinea-pig complement, heat-inactivated serum samples from 9 out of 13 myasthenic patients showed clear rnyotoxicity in contrast to 0 out of 12 normal controls and 0 out of 6 polymyositis patients. Neither heat-inactivated sera alone nor guinea-pig complement alone showed myotoxicity. A further study defined new conditions under which previously 'non-toxic' myasthenic serum samples demonstrated myotoxicity. Removal of anti-AChR antibodies from a myasthenic serum sample by affinity absorption led to a loss of complement-mediated myotoxicity. Finally, studies were carried out in which IgG or IgG depleted of subclass 3, was purified from myasthenic serum samples and tested for complement-mediated myotoxicity. The IgG fractions caused myotoxicity in a similar manner to the whole serum. The studies were extended to human foetal muscle cells in culture which were shown to be less mature than the cultured rat muscle cells in this study. Attempts were made to define optimal growth conditions for the human foetal muscle cells vitro but these were inconclusive. Comparable complement-mediated myotoxicity by myasthenic serum towards human muscle cultures was not shown. However, manipulation of assay conditions resulted in clear myotoxicity by the 2 myasthenic serum samples tested, relative to normal controls. The results gained from this work support the suggestion that complement-mediated cell damage, initiated by anti-AChR antibodies, may contribute to post-synaptic membrane degeneration in myasthenia gravis.
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Nichols, Philip Paul. "Transcriptional regulation of the human nicotinic acetylcholine receptor." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326016.
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Pinto, Ashwin. "Specificity of autoantibodies in Lambert-Eaton myasthenic syndrome for neuronal calcium channels." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342539.
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Clausen, Lisa K. J. "Effects of beta-2 adrenergic receptor agonists in DOK7 congenital myasthenic syndromes." Thesis, University of Oxford, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.712079.
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Clausen, Lisa. "Effects of beta-2 adrenergic receptor agonists in DOK7 congenital myasthenic syndrome." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:9360c51b-8497-47ca-bd16-e917a3614a25.
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Congenital myasthenic syndromes (CMS) are a rare group of heterogeneous disorders, characterised by compromised neuromuscular transmission and symptoms of fatiguable muscle weakness. CMS is caused by mutations in genes that affect the structure and function of the neuromuscular junction (NMJ). In about 20% of CMS cases, patients have mutations in the gene DOK7; the protein product, DOK7, is crucial for maintaining the dense aggregation of acetylcholine receptor (AChR) clusters at the NMJ. DOK7-CMS patients do not respond to treatment with acetylcholinesterase inhibitors which are the first line treatment for most forms of CMS. Instead, a dramatic response to beta-2 adrenergic receptor (ADRB2) agonists, such as salbutamol, is observed. The aim of this project was to investigate the molecular mechanisms that underlie the beneficial effects of ADRB2 agonists. Firstly, NMJ functioning was modelled in vitro by studying AChR clusters formed on cultured C2C12 mouse myotubes in the presence of WT DOK7. Overexpression of mutant DOK7 led to a significant reduction in the number of AChR clusters, explaining the pathogenic effect of the mutation. Importantly, incubation of myotubes with salbutamol increased the number of AChR clusters and their stability. The results provide the first evidence that ADRB2 agonists directly affect proteins located at the NMJ. However, this disease model suffers from limitations. The rest of the thesis focussed on developing alternative cell culture models to explore the AChR clustering pathway. The first model combined optogenetics and fluorescence lifetime microscopy to study the effects of ADRB2 activation on AChR cluster stability in single live cells. The second used CRISPR/Cas9 genome editing tools to directly introduce Dok7 mutations to the genome of C2C12 cells, thereby overcoming some of the drawbacks associated with DOK7 overexpression. Further manipulations of these novel model systems will be used in the future to examine in more detail the molecular events underlying the pathogenic effects of DOK7 mutations and the mechanisms of ADRB2 agonists.
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Ealing, John. "The use of catalytic nucleic acids in the treatment of congenital myasthenic syndromes." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393481.
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Domville, Jaimee Allison. "Mapping the Allosteric Pathway Leading from a Mutation in the Nicotinic Acetylcholine Receptor to a Congenital Myasthenic Syndrome." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/37037.
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The peripheral and highly lipid-exposed M4 α-helix, although distant from the agonist binding site, channel gate, and other important gating structures, is involved in modulating function of the nicotinic acetylcholine receptor. M4 "senses" changes in the surrounding lipid environment and may consequently affect receptor function by altering specific interactions between the M4 C-terminus and the Cys-loop. An example of this lipid sensing ability is demonstrated by a lipid-facing Cys418 to Trp substitution on αM4 (αM4 C418W) of the muscle-type receptor, which subtly alters protein-lipid interactions and potentiates channel function 16-fold, leading to a slow-channel congenital myasthenic syndrome. Through the use of mutational studies and mutant cycle analysis, I determine that, contrary to previous studies, M4–Cys-loop interactions are not critical to wild-type muscle-type receptor function, nor are they involved in C418W-induced potentiation. Instead, C418W potentiates channel activity by enhancing local M4-M1 interactions mediated by three polar side-chains, which are absolutely critical to potentiation. I show that altered M4-M1 interactions are ultimately translated to two important gating structures, which work in tandem to stabilize the open conformation of the receptor. These studies highlight how altered protein-lipid interactions can affect channel function and contribute to our understanding of the underlying gating mechanism of the muscle-type receptor.
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Maddison, Paul. "A quantitative study of the immune-mediated neuromuscular disorders of acquired neuromyotonia and Lambert-Eaton myasthenic syndrome." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285378.
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Cruz, Pedro M. Rodríguez. "Undefined myasthenias : clinical and molecular characterisation and optimised therapy." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:90f1b53c-a5ec-4fe3-8589-8ea076fc4cbf.
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Congenital myasthenic syndromes (CMS) are a group of heterogeneous disorders caused by mutations in genes encoding for proteins that are essential for neuromuscular transmission. All CMS share the clinical feature of fatigable muscle weakness. The differential diagnosis of CMS is wide, with a range of diseases going from autoimmune myasthenia gravis to muscle disorders. In this thesis, it was shown that measuring antibodies to clustered acetylcholine receptors (AChRs) by cell-based assay is helpful in the differential diagnosis of CMS. The findings of the current investigations showed that mutations in COL13A1, encoding the Collagen Type XIII α1 chain, were responsible for the symptoms of several patients with previously undefined myasthenias. In addition, this work described the clinical and complementary features of a novel CMS subtype due to mutations in the glycosylation pathway gene GMPPB. Investigations on a novel MUSK missense mutation (p.Ala617Val) uncovered previously unrecognised mechanisms of how levels of MuSK phosphorylation are critical to maintain synaptic structure, and guided suitable treatment for the patient. The study on the clinical and molecular basis of stridor, a novel clinical feature recently identified in patients with DOK7-CMS, prompted the identification of a novel DOK7 isoform, which warrants further investigation to elucidate its role in AChR clustering. Finally, the therapy of patients with severe AChR-deficiency was optimised thanks to a case series study that showed a robust improvement following the addition of β2-adrenergic agonists to their long-term treatment regime that included pyridostigmine.
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Duffield, Michael. "Comparison of the expression pattern of voltage-gated calcium channel subunits and Lambert-Eaton myasthenic syndrome autoantibodies in the mouse colon /." Adelaide, 1999. http://web4.library.adelaide.edu.au/theses/09SB/09sbd857.pdf.
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von, Rosch Anthony Stanislav Wierzbicki. "The isolation and characterisation of the genes coding for the calcium channel affected by Lambert-Eaton myasthenic syndrome antibodies in NG108-15 cells." Thesis, University of Oxford, 1992. https://ora.ox.ac.uk/objects/uuid:096b02c9-8c80-4f82-8d4c-8ed2ca59aa2e.
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Lambert-Eaton myasthenic syndrome is a rare paraneoplastic and autoimmune disorder affecting the presynaptic voltage gated calcium channels at the neuromuscular junction. The aim of this project was to isolate the genes coding for the α1 and α2 subunits of the voltage-gated calcium channel from hybrid neuronal cell lines including NG108-15 whose potassium stimulated <sup>45</sup>Ca<sup>2+</sup> flux is reduced by IgG from patients with Lambert-Eaton myasthenic syndrome. The cDNA libraries were constructed in λgt10 from NG108-15 mRNA and screened with PCR products derived from the rabbit skeletal muscle α1 and α2-δ genes. A 2230 bp portion of the NG108-15 α2-δ gene homologous to bp 1000- 3304 of the rabbit gene has been isolated and sequenced. This shows 48% homology to the amino acid sequence of the rabbit gene and 56% nucleotide homology with particular conservation of the C-tenninal domains. The NG108-l5 α2 mRNA is 8.5 kb long and was found in the N18TG2 mouse neuroblastoma cell line from which NG108-15 is derived and in mouse brain. Rabbit α2-δ gene PCR primers were used to screen a rodent tissue cDNA panel to detect highly homologous sequences by PCR amplification. These products were detected only in mouse brain and lung and in rat skeletal muscle. The mouse brain and lung product amino acid sequences were 87% homologous to the rabbit gene while the rat skeletal muscle product was 81% homologous and both differed significantly from the homologous region of the NG108-15 gene. This suggests that some of the diversity of voltage gated calcium channels arises from the expression of different α2-δ subunits within the 5 subunit VGCC complex as well as from diversity in the other subunits.
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Trecenti, Anelize de Souza. "Investigação das mutações responsáveis pela doença de acúmulo de glicogênio tipo II e pela miastenia hereditária em bovinos da raça Brahman no Brasil." Universidade Estadual Paulista (UNESP), 2017. http://hdl.handle.net/11449/152155.
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Previous issue date: 2017-11-01<br>Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)<br>A doença de acúmulo de glicogênio tipo II (GSD-II) e a síndrome miastênica congênita (CMS) são enfermidades autossômicas recessivas importantes no gado Brahman. Nenhum estudo avaliou previamente a prevalência de mutações responsáveis pelo GSD II (E7, c.1057_1058delTA e E13, c.1783C> T) ou CMS (CHRNE, c.470del20) nos bovinos Brahman brasileiro. O objetivo deste estudo foi investigar a presença dessas mutações em 276 amostras de bulbos pilosos de bovinos PO brasileiros e em 35 amostras de sêmen de touros da raça Brahman, rotineiramente utilizadas em programas de melhoramento genético no Brasil. Dos 276 bovinos Brahman testados, 7,3% foram identificados como heterozigotos para E7. Enquanto, todos os bovinos Brahman estudados eram wild-type para E13. Para as amostras de sêmen foi identificado 8,6% (3/35) heterozigotos para a E7 e para a E13 nenhum animal foi identificado. A mutação CHRNE, 0,73% das amostras de bulbo piloso são heterozigotos, enquanto para as amostras de sêmen, nenhum animal foi considerado heterozigoto. Este resultado indica que as mutações E7 e CHRNE estão presentes no rebanho Brahman brasileiro, e medidas de controle devem ser adotadas para evitar um aumento na incidência de GSD-II e CMS no gado Brahman no Brasil.<br>Glycogen storage disease type II (GSD-II) and congenital myasthenic syndrome (CMS) are important autosomal recessive disorders in Brahman cattle. No study has previously evaluated the prevalence of mutations responsible for GSD II (E7, c.1057_1058delTA; and E13, c.1783C>T) or CMS (CHRNE, c.470del20) in Brazilian Brahman cattle. The objective of this study was to investigate the presence of these mutations in 276 hair roots from purebred Brazilian Brahman cattle and in 35 semen samples from purebred Brahman bulls that were routinely used in breeding programmes in Brazil. Of the 276 Brahman cattle tested, 7.3% were identified as heterozygous for E7. All Brahman cattle studied were homozygous for the wild-type E13 allele. The E7 mutations was identified as heterozygous in 8.6% (3/35) of the commercial semen samples, whereas the E13 mutations was not identified. The CHRNE mutation was identified as heterozygous in 0.73% of the hair root samples, but this mutation was not present in any semen sample assessed. In summary, the E7 and CHRNE mutations are present in the Brazilian Brahman herd, and control measures should be adopted to prevent an increase in the incidence of GSD-II and CMS in Brahman cattle in Brazil.<br>432/2014
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da, Silva Leite Maria Isabel. "Myasthenia Gravis: Investigations into Seronegative Myasthenia." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490100.
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Myasdienia gravis (MG) is an antibody-mediated autoimmune disease causing muscle weakness and fatigue. Over 80% of patients with generalised MG have IgG autoantibodies (mostly IgUlj to the native muscle acetylcholine receptor (AChR) at the neuromuscular junction (NM]). AChR-antibody-positive MG (AChR-MG) patients often benefit from thymectomy. Their thymus usually has epithelial hyperplasia and the thymus is thought to be the site of autoimmunisation against AChR. Of the remaining 15-20% of patients with generalised MG, a variable proportion (0-50%) have autoantibodies to muscle-specific kinase, MuSK (MuSKMG), which are predominantly IgG4. These patients usually have more severe disease, which does not respond to thymectomy, but their thymic pathology has not been studied in detail. The remaining patients have no detectable autoantibodies against AChR or MuSK (seronegative MG, SNMG), but have similar disease to AChR-MG, although tending to be milder, and it is not clear whether the thymus is also abnormal.
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Simpson, John Alexander. "Myasthenia gravis." Thesis, University of Edinburgh, 1991. http://hdl.handle.net/1842/27395.
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The thesis is 72 publications describing the author's hypothesis of an autoimmune basis for myasthenia gravis (MG) and its validation. At the time of the first 24 papers many considered that MG was a syndrome rather than a disease entity, due to a biochemical disorder of the neuromuscular junction. Favoured models were a circulating 'curare-like' substance released from the thymus gland, or a pre-junctional abnormality, possibly causing release of small quanta of acetylcholine at the motor nerve terminals. Endplate receptor substance was speculative. The immunological role of the thymus was unknown and autoimmunity was a new concept in medicine. The therapeutic value of thymectomy was controversial. The controversy about thymectomy was resolved (papers 2,3) by re-analysing data separately for patients with a thymona and the conclusions have proved definitive. Papers based on the cases reviewed in that survey led to an autoimmune hypothesis with a thymic disorder causing production of antibodies with loss of tolerance to self-tissue, mainly but not exclusively at the motor endplates of muscle. The first recognition of many associated diseases and a re-interpretation of the relationship with thyroid disorders are described, with the first evidence for a genetic predilection with alternative expression. During the 35 years of this work the distinct nature of 'carcinomatous' myasthenia has been identified, and the non-immunological congenital myasthenias defined by other workers.
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Armbruster, Lena. "Lambert-Eaton Myasthenie Syndrom." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-112592.
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Verschuuren, Johannes Justus Gerard Maria. "Experimental autoimmune myasthenia gravis." Maastricht : Maastricht : Datawyse ; University Library, Maastricht University [Host], 1989. http://arno.unimaas.nl/show.cgi?fid=5471.
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Robb, S. A. "T cells in myasthenia." Thesis, University of Newcastle Upon Tyne, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376234.
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Schaffert, Hanne. "Immunpathogenese der Myasthenia gravis." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2015. http://dx.doi.org/10.18452/17213.
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Die Myasthenia Gravis (MG) ist ein Prototyp einer Antikörper-vermittelte Autoimmunerkrankung. Die Autoantikörper richten sich hauptsächlich gegen den Acetylcholinrezeptor (AChR). Welche Bedeutung TH17-Zellen für die Pathogenese der MG haben, konnte bisher noch nie direkt gezeigt werden. Mithilfe des Tiermodells Experimentelle Autoimmune Myasthenia Gravis (EAMG) sollte die Rolle der TH17-Zellen im Rahmen dieser Arbeit analysiert werden. Eine signifikante Anzahl tAChR-spezifischer CD4+ T-Zellen, die IL17 exprimieren, konnte nach der Immunisierung mit torpedo AChR in CFA in Wildtyp-Mäusen (WT) beobachtet werden. Die IL17ko Mäuse entwickelten weniger oder keine EAMG Symptome, obwohl weder die Frequenz tAChR-spezifischer CD4+ T-Zellen, die IL2, IFNgamma oder IL21 sezernierten noch der prozentuale Anteil der FoxP3+ Treg-Zellen einen Unterschied aufwiesen. Im Gegensatz dazu waren die Level pathogener anti-muriner AChR Antikörper statistisch geringer in IL17ko Mäusen, während bei anti-tAChR Antikörpertitern kein Unterschied festzustellen war. Ähnliche Resultate erbrachten TCRbeta/delta ko Mäuse rekonstituiert mit entweder WT oder IL17ko CD4+ T-Zellen. Die Depletion von Treg-Zellen mithilfe von DEREG Mäusen in der frühen Erkrankungsphase zeigte keine signifikanten Unterschiede bezüglich der analysierten Parameter. Zusammenfassend lässt sich hier festhalten, dass die Frequenz und Differenzierung Antigen-spezifischer CD4+ T-Zellen sowie der Antikörpertiter gegen den tAChR nicht durch die IL17-Defizienz im EAMG Modell beeinflusst wird. Auch hat eine frühe Treg-Zell-Depletion keinen Einfluß auf die Erkrankungsstärke. Allerdings scheint das Durchbrechen der B-Zell Toleranz, das zur Produktion von pathogenen Anti-mAChR-spezifischen Antikörpern und somit zu einer Induktion der Erkrankung führt, abhängig von IL17-produzierenden CD4+ T-Zellen zu sein. Der Einsatz von Anti-IL17-Antikörpern könnte insofern auch für die MG eine Therapieoption darstellen.<br>Myasthenia gravis (MG) is an antibody-mediated autoimmune disease. The autoantibodies are directed against the acetylcholine receptor (AChR). The importance TH17 cells have for MG pathogenesis has never been directly demonstrated. Therefore, the analysis of TH17 cells in the Experimental Autoimmune Myasthenia Gravis (EAMG) animal model was the aim of this work. Here, it is shown that in wildtype mice (WT) significant numbers of IL17-producing tAChR-specific CD4+ T cells could be observed after immunization with torpedo AChR in CFA. IL17ko mice developed less or no EAMG symptoms, although frequencies of tAChR-specific CD4+T cells secreting IL2, IFNgamma or IL21 as well as percentage of FoxP3+ Treg cells were similar. In contrast, pathogenic anti-murine AChR antibody levels were significantly lower in IL17ko mice, while anti-tAChR antibody levels were equal. Similar results were obtained by the reconstitution of TCR beta/delta ko mice with CD4+ T cells of either WT or IL17ko origin. For the depletion of Treg cells using DEREG mice in the initial phase of the disease no significant differences could be detected in terms of the analyzed parameters. In summary, this thesis demonstrates, that frequencies and differentiation of antigen specific CD4+ T cells as well as the level of anti-tAChR specific antibody titers are not affected by IL17-deficiency in the EAMG model. Likewise, an early Treg cell depletion seems to have no impact on disease severity. However, breaking of B cell tolerance resulting in pathogenic anti-murine AChR specific antibodies and subsequent disease induction, seems to be dependent on IL17 producing CD4+ T cells. In this respect, the application of anti-IL17 antibodies could also become a MG therapy option.
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Kaufman, Robin L. "Immunoregulation in myasthenia gravis." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/30683.
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Myasthenia Gravis (MG) is an autoimmune disorder of neuromuscular transmission. Clinically, the disease is manifested by abnormal muscle fatigue with recovery on resting. Circulating nicotinic acetylcholine receptor antibodies (nAchR Ab) are highly characteristic of myasthenia gravis. These antibodies have been shown to be directly pathogenic at the muscle endplate and are responsible for impaired neuromuscular transmission through several mechanisms.
While it is clear that the immune system does not function normally in MG, the mechanisms by which the response to nAchR is initiated and perpetuated remain unknown. Moreover, it is not clear whether immunoregulatory defects actually precede development of MG or are secondary features of the disease. The overall goal of the present investigation has been to more clearly define the nature of the immune regulatory defects existing in MG, both at the cellular level and in terms of possible relationship to disease progression.
To begin these studies it was necessary to develop an assay that could be used to measure nAchR Ab secreted by lymphocytes in culture. Thus, we modified the original nAchR Ab immunoassay described by Lindstrom (1976) for this purpose. Additionally, in order to gain access to an appropriate patient base for our study, we established a further modification with improved sensitivity for detection of serum nAchR Ab. This important diagnostic test had not been available in this country. Therefore, our assay was made available in Canada for clinical purposes.
Through the study of in vitro nAchR Ab and polyclonal IgG secretion by peripheral blood mononuclear cells (PBMNC), we were able to identify two previously unrecognized subgroups of seropositive, generalized MG patients. PBMNC from patients with long disease duration had low capacity for in vitro Ab production (Nonsecretors). Among patients of short disease duration, PBMNC produced nAchR Ab and also secreted higher than normal levels of polyclonal IgG (Secretors). The data suggested that there were nonspecific abnormalities affecting the immune response in myasthenia gravis. Moreover, regulation of B lymphocyte mediated immune function appeared to be related to disease progression.
It was hypothesized that circulating auto-antibody may contribute to deregulation of the immune response at certain stages of disease through direct interactions with leukocyte determinants. Separation/reconstitution experiments with CD4+ enriched, T-helper/inducer lymphocytes and B enriched (E- cells) lymphocytes suggested that the control of antibody production in myasthenia gravis was operative at the T-helper/inducer level. Preliminary studies with serum pretreated, CD4+ enriched, T-helper/inducer lymphocytes suggested that serum of Secretor MG patients indeed contained a factor(s) which interfered with the function of a CD4+ lymphocyte subset.
We further hypothesized that nAchR Ab would have the potential to behave as anti-lymphocyte Ab if nAchR were expressed on lymphocytes. Accordingly, direct binding studies, using the nicotinic antagonist, alpha-bungarotoxin, were carried out to look for such receptors on PBMNC. Specific, saturable binding of alpha-bungarotoxin to the rhabdomyosarcoma cell line, TE671, was confirmed and characterized. However, in parallel studies, alpha-bungarotoxin binding to PBMNC of healthy individuals or MG patients was not detected. These results suggested that nicotinic acetylcholine receptors, of the type expressed by muscle endplate, do not occur on human peripheral blood mononuclear cells.<br>Medicine, Faculty of<br>Pathology and Laboratory Medicine, Department of<br>Graduate
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McConville, John Paul. "Autoantibodies in seronegative myasthenia gravis." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400295.
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EL, KHAILI HASSAN. "Myasthenie, myasthenie grave experimentale auto-immune et syndromes myastheniques induits par l'alphabungarotoxine : effets des glucocorticoides." Strasbourg 1, 1991. http://www.theses.fr/1991STR15068.
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Härönen, H. (Heli). "Collagen XIII as a neuromuscular synapse organizer:roles of collagen XIII and its transmembrane form, and effects of shedding and overexpression in the neuromuscular system in mouse models." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526218014.
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Abstract Collagen XIII is a transmembrane protein consisting of intracellular, transmembrane and extracellular domains. The latter can be cleaved by proteases of the furin family at the plasma membrane and in the trans-Golgi network. Both the transmembrane and shed collagen XIII are expressed at the neuromuscular junctions of mice and humans. Such motor synapse passes the contraction signal from the central nervous system to the muscles and brings about all voluntary movements. Loss of both forms of collagen XIII in mice and loss-of-function mutations in the COL13A1 gene in humans leads to congenital myasthenic syndrome characterized by decreased neuromuscular transmission and muscle weakness. To study the roles of the two collagen XIII forms, a novel mouse line was engineered to harbor only the transmembrane collagen XIII by mutating the furin cleavage site. Transmembrane collagen XIII was discovered to be sufficient to prevent adhesion defects, Schwann cell invagination, the ineffective vesicle accumulation and dispersion of both acetylcholinesterase and acetylcholine receptors, phenotypes seen in the complete lack of collagen XIII. On the other hand, lack of shedding led to acetylcholine receptor fragmentation, aberrantly increased neurotransmission and presynaptic complexity. Remarkably, in vivo and in vitro interaction of collagen XIII and acetylcholinesterase-anchoring ColQ was detected. Furthermore, muscle and neuromuscular junction phenotype in the lack of both forms of collagen XIII closely resembled those in the human patients harboring mutations in the COL13A1 gene and these mice were validated as a good model for studying the human disease. Misexpression of collagen XIII was studied with mice exhibiting transgenic overexpression of the protein. Overexpression of collagen XIII was detected to be mostly extrasynaptic in the muscles of such mice. Exogenous collagen XIII was found at the myotendinous junctions, tenocytes and fibroblast-like cells, in addition to some localization in the near vicinity of the neuromuscular junctions. Collagen XIII expression was found, for the most part, to be normal at the neuromuscular junctions, although some were devoid of collagen XIII. The neuromuscular junction phenotype resembled in many ways the findings made in the lack of collagen XIII. Furthermore, acetylcholine receptor and nerve pattern was discovered to be widened<br>Tiivistelmä Kollageeni XIII on solukalvoproteiini, jonka rakenne koostuu solunsisäisestä, solukalvon läpäisevästä ja solun ulkoisesta osasta, joka pystytään entsymaattisesti irrottamaan solukalvoilta. Täten se esiintyy kahdessa eri muodossaan; solukalvomuotoisena ja soluvälitilan lihasperäisenä proteiinina hiirten ja ihmisten hermolihasliitoksessa. Tässä motorisessa synapsissa keskushermostosta peräisin oleva lihaksen supistumiskäsky välittyy lihakseen ja aikaan saa tahdonalaiset liikkeet. Molempien kollageeni XIII:n muotojen puute hiirillä ja COL13A1 geenin mutaatiot ihmisillä johtavat synnynnäiseen myasteeniseen oireyhtymään, jossa heikentynyt hermolihasliitoksen toiminta johtaa lihasheikkouteen. Kollageeni XIII:n eri muotojen hermolihasliitosvaikutusten selvittämiseksi luotiin hiirilinja, jossa kollageeni XIII ilmenee geneettisen manipulaation seurauksena ainoastaan solukalvomuodossaan. Tutkimukset osoittivat solukalvomuotoisen kollageeni XIII:n tarvittavan hermon ja lihaksen kiinnittymiseen toisiinsa, hermovälittäjäainerakkuloiden ankkuroimiseen hermopäätteeseen, estämään Schwannin solujen tunkeutuminen synapsirakoon, asetyylikoliiniesteraasin sitomiseen ja asetyylikoliinireseptorien vakaantumiseen. Soluvälitilan kollageeni XIII:n puutos puolestaan johti lihaksen puolen liitoksen pirstaloitumiseen sekä hermopäätteiden liialliseen kasvuun ja aktiivisuuteen. Kollageeni XIII todettiin sitoutuvan asetyylikoliiniesteraasia hermolihasliitokseen ankkuroivan kollageeni Q:n kanssa. Lisäksi molempien kollageeni XIII:n muotojen suhteen poistogeenisten hiirten hermolihas- ja lihaslöydökset todettiin muistuttavan COL13A1 geenin mutaatioista kärsivien ihmisten vastaavia löydöksiä todistaen nämä hiiret hyväksi tautimalliksi tulevaisuuden hoitomuotojen suunnitteluun. Kollageeni XIII:n ylimäärän vaikutusta hermolihasliitokseen ja lihaskudokseen tutkittiin kollageeni XIII:a ylenmäärin ilmentävillä hiirillä. Kollageeni XIII todettiin ilmentyvän ylenmäärin lihaksessa fibroblastinkaltaisissa soluissa, lihasjänneliitoksessa ja hermolihasliitoksen lähettyvillä, mutta ei hermolihasliitoksessa. Osa hermolihasliitoksista näissä hiirissä ilmensi jopa vähemmän kollageeni XIII:a kuin normaalisti. Asetyylikoliinireseptorien ja hermojen valtaama alue todettiin leventyneeksi ja hermolihasliitoslöydökset muistuttivat molempien kollageeni XIII:n muotojen suhteen poistogeenisien hiirten löydöksiä
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Labouret, Pascale. "Etude rétrospective de 67 patients myasthéniques." Université Louis Pasteur (Strasbourg) (1971-2008), 1991. http://www.theses.fr/1991STR1M116.
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Wang, Hua-Bing. "Immunoregulation in experimental autoimmune myasthenia gravis /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4437-7/.
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Buckley, Camilla. "Autoimmunity in thymoma-associated Myasthenia gravis." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394014.
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Burke, Georgina. "Genotype - phenotype correlations in congenital myasthenia." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437178.
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Betty, Maria. "Molecular genetic studies in hereditary myasthenia." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240536.
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RAVEL, CHRISTOPHE. "Myasthenie et pathologies auto-immunes associees." Clermont-Ferrand 1, 1992. http://www.theses.fr/1992CLF13029.
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Pereira, Antonio. "Myasthenia gravis : l'histoire de madame h." Lille 2, 1988. http://www.theses.fr/1988LIL2M375.
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Koneczny, Inga. "Potential mechanisms in MuSK-myasthenia gravis." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:7b81b941-92c0-47ae-a747-62277394638e.
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Autoimmunity is a failure to tolerate circulating or cell surface expressed self antigens,leading to activation of the immune system and attack of self tissues. Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a disease caused by antibodies to MuSK and hallmarked by fatigable muscle weakness. MuSK is a tyrosine kinase that interacts with low-density lipoprotein receptor-related protein 4 (LRP4), resulting in maintenance of the high density of acetylcholine receptors (AChRs) at the neuromuscular junction; this high density is essential for efficient transmission of signals from nerve to muscle, and MuSK antibodies impair this transmission. MuSK antibodies are predominantly IgG4, a subclass that does not induce immunological damage. Thus how these antibodies cause neuromuscular junction dysfunction is not clear. Potential mechanisms of the MuSK antibodies were explored in in vitro experiments. Plasmas from fourteen MuSK-MG patients were studied. IgG antibodies and IgG subclass profiles were measured with flow cytometry. Total IgG, Fabs, IgG4 and IgG1-3 subclass antibodies were prepared and purified; these were used to investigate the effects on MuSK surface expression, binding of LRP4 to MuSK, and agrin-LRP4-MuSK-induced AChR clustering in C2C12 mouse myotubes. No evidence for MuSK endocytosis by MuSK IgG, IgG1-3 or IgG4 antibodies was found. The predominant IgG4 subclass, and the monovalent IgG Fabs, blocked binding between LRP4 and MuSK but both IgG4 and IgG1-3 subclass antibodies were equally able to disperse pre-formed and newly-induced AChR clusters in C2C12 myotubes. The block of LRP4-MuSK interaction by IgG4 antibodies is likely to be a major pathogenic mechanism in MuSK-MG, which may lead to disrupted signal transduction, reduced AChR aggregation and neuromuscular transmission failure at the neuromuscular junction. In addition, MuSK IgG1-3, until now described as nonpathogenic, may also contribute to the reduced AChR density and neuromuscular dysfunction in MuSK-MG. These results provide new evidence concerning the pathogenic antibodies and their mechanisms in MuSK-MG.
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Gärtner, Sabine Luise. "Kongenitale myasthene Syndrome." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-87075.
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Shi, Fu-Dong. "Immunopathogenesis and nasal tolerance in experimental autoimmune myasthenia gravis /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980525shi.
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Glasner, Stefan. "Wirbelsäulendegeneration und Muskelschwäche eine Studie zur Spondylolisthesis und zu myopathologischen Befunden des Musculus erector spinae." Berlin dissertation.de, 2005. http://d-nb.info/98988385X/04.
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MARTINENT, LOUIS. "Place de la radiotherapie dans le traitement de la myasthenie : a propos de 30 observations." Lyon 1, 1990. http://www.theses.fr/1990LYO1M439.
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PLUCHON, YVES-MARIE. "Evolution des conceptions therapeutiques dans la myasthenie generalisee : a propos de 29 observations recueillies sur 20 ans dans le service de neurologie du c.h.r.u. de nantes." Nantes, 1988. http://www.theses.fr/1988NANT144M.
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WADOUX, SYLVIE. "Myasthenie grave : a propos d'un cas clinique ; etude du mecanisme physiopathologique." Amiens, 1994. http://www.theses.fr/1994AMIEM120.
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Mayer, Anne. "Antibiotiques contre-indiques dans le traitement de la myasthenie." Strasbourg 1, 1991. http://www.theses.fr/1991STR15076.
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VILQUIN, JEAN-THOMAS. "Contribution a la comprehension, au traitement et au diagnostic de la myasthenia gravis." Strasbourg 1, 1992. http://www.theses.fr/1992STR15067.
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Messéant, Julien. "Rôle des protéines Wnt et de leurs voies de signalisation associées dans la formation de la jonction neuromusculaire." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T068.
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La formation de la jonction neuromusculaire des vertébrés (JNM), une synapse cholinergique périphérique entre les motoneurones et les fibres musculaires squelettiques repose sur la reconnaissance et l’apposition précise des motoneurones présynaptiques sur leurs cibles musculaires postsynaptiques. Les données de la littérature montrent que les morphogènes Wnt agissent comme des régulateurs clés de la formation de la JNM. Cependant, l'identité précise des Wnts, leur collaboration et les mécanismes moléculaires de la signalisation Wnt régissant la formation de la JNM restent encore incompris. A la JNM, la transduction du signal Wnt s’effectue par l'intermédiaire de l’interaction des Wnt soit avec le complexe formé par le récepteur tyrosine kinase MuSK et la lipoprotéine Lrp4 ou les récepteurs classiques Frizzled (Fzd). Dans cette thèse, nous avons étudié les mécanismes moléculaires de la formation de la JNM médiés par les Wnts. Nous avons montré que Wnt4 et Wn11 sont nécessaires pour l’étape indépendante du nerf de prepatterning musculaire, caractérisée par l’agrégation des récepteurs de l’acétylcholine (RACh) dans des domaines discrets de la surface du muscle où la future synapse va se former, via l'activation différentielle des voies canonique et polarité cellulaire planaire (PCP). De plus, Fzd3 et Vangl2, deux composantes essentielles de la voie PCP, sont accumulées à la JNM et sont impliquées distinctement dans la formation de la JNM, Fzd3 étant nécessaire à la croissance des axones moteurs alors que Vangl2 joue un rôle dans l’agrégation du RACh et la restriction de la croissance des axones moteurs une fois leur cible musculaire atteinte. Pour étudier le rôle fonctionnel de l'interaction Wnt/MuSK, nous avons généré une souris transgénique délétée du domaine de liaison de MuSK aux Wnts (CRD, domaine riche en cystéines). Nous avons démontré que l'absence du CRD de MuSK affecte la formation de la JNM dès l’étape deprepatterning jusqu’à la maintenance de la JNM chez l’adulte, aboutissant à un phénotype pathogène. De plus, nous avons montré que le lithium, un inhibiteur réversible de la glycogène synthase kinase-3 restaure les défauts de formation de la JNM chez les embryons mutants et pourrait constituer un nouveau réactif thérapeutique pour le traitement des maladies neuromusculaires liées à une déficience de la voie de signalisation Wnt/MuSK<br>Formation of the vertebrate neuromuscular junction (NMJ), a peripheral cholinergic synapse between motoneurons and skeletal muscle fibers relies on the accurate recognition and apposition of presynaptic motoneurons on postsynaptic muscle target. Recently, a growing body of evidence indicates that Wnt morphogens act as key regulators of NMJ formation. Yet, the specific Wnts identity, their collaborative function and the downstream molecular mechanisms of Wnt signaling regulating NMJ formation still remain elusive. At the NMJ, Wnt ligands transduce their signal through interaction of either the receptor complex formed by the muscle specific tyrosine kinase MuSK and the low density lipoprotein (Lrp) Lrp4 or the classical frizzled receptors. In this thesis, we have investigated the molecular mechanisms of Wnt-induced NMJ formation. We found that both Wnt4 and Wn11 are required for the nerve-independent muscle prepatterning step, characterized by acetylcholine receptor (AChR) aggregation in discrete domains of the muscle surface where the synapse will form, via differential activation of either canonical and/or planar cell polarity (PCP) pathways. Moreover, Fzd3 and Vangl2, two core components of the PCP pathway, are accumulated at the developing NMJ and play distinct roles in NMJ formation, with Fz3 required for motor axon growth and Vangl2 involved in AChR clustering and motor axon growth restriction within the target field. To further study the functional role of Wnt/MuSK interaction, we generated a transgenic mice deleted from MuSK Wnt binding domain (CRD, cysteine rich domain). We demonstrated that the absence of MuSK CRD affected NMJ formation from the prepatterning step to NMJ maintenance in adult leading to a pathogenic phenotype. Moreover, we found that lithium, a reversible inhibitor of the glycogen synthase kinase-3 fully rescued NMJ defects in mutant embryos and therefore may constitutes a novel therapeutic reagent for the treatment of neuromuscular disorders linked to Wnt/MuSK signaling pathway deficiency
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Xu, Biying. "Studies of immune mechanisms in myasthenia gravis /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3265-4/.
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Plested, Charles Paul. "Mechanism of action of seronegative myasthenia gravis." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301392.
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Moody, Anne Marie. "T-cell receptor studies in myasthenia gravis." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337448.
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Croxen, Rebecca. "Molecular genetic studies in hereditary/congenital myasthenia." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267938.
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