Duchenne muscular dystrophy (DMD) is a disease, characterized by progressive muscle wasting, caused by the lack of Dystrophin. A subset of DMD patients also have cognitive deficits likely due to... Show moreDuchenne muscular dystrophy (DMD) is a disease, characterized by progressive muscle wasting, caused by the lack of Dystrophin. A subset of DMD patients also have cognitive deficits likely due to the absence of Dystrophin from brain synapses where it is usually localized. Dystrophin and a number of other conserved proteins form the so-called Dystrophin Glycoprotein Complex (DGC). Here, I explored how the absence of DGC proteins might cause cognitive impairment by examining the roles of DGC members at peripheral and central synapses in the Drosophila model system. We found that the Rho-GAP crossveinless-c (cv-c) gene, which encodes a negative regulator of Rho-GTPase pathways, genetically interacts with Dystrophin. Both the cv-c1 and Dystrophin DLP2 mutants display increased presynaptic neurotransmitter release. We showed that the Rho-GTPase CDC42 is an important substrate of CV-C in this pathway. Furthermore, we de monstrated that it is the delocalization of the DGC protein Dystrobrevin in the absence of Dystrophin which causes the phenotype. We conclude that postsynaptic Dystrophin and this Rho-GTPase signaling pathway interact to regulate the synaptic homeostatic endpoint of neurotransmitter release. We hope that our findings may provide insights for the development of novel approaches to treat the cognitive deficits in DMD patients Show less
The Guillain-Barr_ syndrome (GBS) is an acute, post-infectious neuropathy. Several clinical presentations are known, but general symptoms are symmetric muscle weakness and loss of tendon reflexes.... Show moreThe Guillain-Barr_ syndrome (GBS) is an acute, post-infectious neuropathy. Several clinical presentations are known, but general symptoms are symmetric muscle weakness and loss of tendon reflexes. In more than half of the GBS patients, antibodies against gangliosides can be detected in their serum. Gangliosides are glycosphingolipids, which are located in the outer layer of cell membranes, and play a role in cell-cell recognition and communication. Because gangliosides are highly enriched in the presynaptic nerve membranes, a role in synaptic transmission and the process of neurotransmitter release is assumed. We explored the physiological role of these gangliosides in transmitter release in neuromuscular synapses of mice using electrophysiological techniques. Furthermore, these synapses were also studied for the pathophysiological effects caused by antibodies against the gangliosides. The results show that gangliosides appear not to be fundamental for neuromuscular function, but rather have a modulating role. In addition, blocking of the complement system, using complement-component C5-inhibitors, is an effective method to protect the nerve membrane against the damaging effects of the activated complement system as a result of anti-ganglioside antibody binding. These and other experimental findings of this thesis are discussed in view of the current literature and the pathogenesis and therapeutical aspects of GBS. Show less
Duchenne Muscular Dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle wasting and sometimes mild mental retardation. The disease is caused by mutations in the... Show moreDuchenne Muscular Dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle wasting and sometimes mild mental retardation. The disease is caused by mutations in the dystrophin gene. DMD is correlated with the absence of Dp427, which is located along the sarcolemma in skeletal muscle where it is part of a large protein complex, the Dystrophin Glycoprotein Complex (DGC). A number of working hypotheses, based on studies from many laboratories, have been raised over the past decades, but the exact functions of the DGC are still largely unclear. The aim of our research is to dissect the fundamental, and likely evolutionarily conserved, functions of Dystrophin and the DGC in Drosophila. This thesis demonstrates different roles for Drosophila Dystrophin isoforms in the same tissue as well as apparently similar roles for two isoforms in different tissues. We have uncovered novel roles for two Dystrophin isoforms in regulating synaptic transmission via a retrograde signal. We now strive to uncover novel interacting proteins by further employing the powerful genetics of the fruit fly . These should help us further the understanding of the mechanisms leading to muscle degeneration and synaptic dysfunction, and may aid discovery of more effective treatments for Duchenne muscular dystrophy. Show less
