Research Report 2010 - MDC

Jochen C. MeierStructure of the GroupGroup LeaderJun.-Prof. Dr. Jochen C. MeierScientistsDr. Sabrina EichlerGraduate StudentsBenjamin FörsteraAline WinkelmannTechnical AssistantsCarola BernertJosephine GroschRNA Editing and HyperexcitabilityDisordersIn a healthy organism, a balance is maintained between the excitation and inhibition ofelectrical impulses generated by neurons in the brain. Deregulation of this balance results innervous system disorders. A core aspect of our work concerns the study of the brain at themolecular level, by investigating post-transcriptional enzymatic processes known in research as"RNA editing" and "splicing". We search for disease-associated alterations in post-transcriptionalprocesses in the nervous system. Within this context, we are more closely scrutinizing glycineand GABA(A) receptors and gephyrin – key components of the molecular machine responsiblefor inhibition of electrical impulses in the brain.Synaptic and tonic inhibition – Glycine receptordynamics from the point of view of gephyrinNeurotransmitter receptors are highly mobile entitieswithin the neuronal plasma membrane. Enrichment ofpostsynaptic domains with neurotransmitter receptorstherefore reflects a dynamic equilibrium between lessmobile, synaptic and highly mobile, non-synaptic receptors.The diffusion rate is slowed down by reversibleglycine receptor binding to the postsynaptic scaffoldingprotein gephyrin. These receptors contribute to synapticinhibition of action potential generation whereashighly mobile receptors, which escaped postsynapticanchoring, are involved in tonic inhibition of neuron firing.In the past, we could identify several novel splicevariants of gephyrin, which were uncovered to adoptspecific functions in the hippocampus. There, certaingephyrin splice variants were identified negative regulatorsof postsynaptic receptor stabilization at inhibitorysynapses, providing us with novel experimentalstrategies for treatment of hyper-excitability disorders,such as temporal lobe epilepsy.Deciphering the molecular basis of Molybdenumcofactor biosynthesisGephyrin has enzymatic activity. It is a multidomainprotein that emerged from fusion of two bacterial proteins,MogA and MoeA. These Escherichia Coli proteinscontribute to the biosynthesis of molybdenum cofactor(Moco), which is an essential component of cellularredox reactions. Mammalian gephyrins are still able tosynthesize Moco because the enzymatic activity of theE. Coli homologous domains is preserved. In mammals,the most important Molybdenum enzyme is sulfite oxidase,which catalyzes the last step in the degradation ofsulfur-containing amino acids and sulfatides. HumanMoco deficiency is a hereditary metabolic disorder characterizedby severe neurodegeneration resulting inearly childhood death. We have identified a numbergephyrin splice variants deficient in Moco synthesis.Therefore, another aspect of our work concerns themolecular and functional dissection of alternativelyspliced gephyrins, using truncated and mutant expressionconstructs in a variety of cell types.168 Function and Dysfunction of the Nervous System