The roles of dystrophin and dystrobrevin : in synaptic signaling in drosophila

Potikanond, S.

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 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...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 patientsShow less

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The roles of dystrophin and dystrobrevin : in synaptic signaling in drosophila

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