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VIB CMN - Molecular Neurogenomics
Main organisation:Department of Biomedical Sciences
Lifecycle:1 Jan 2011 → Today
Organisation profile:The Lab focuses on the identification and characterization of disease-causing genes and pathways implicated in the molecular etiology of neurological disorders, like inherited peripheral neuropathies (CMT) and inherited epilepsies. For this purpose we use two major research strategies:- unraveling the role of aminoacyl-tRNA synthetases in peripheral neurodegeneration as a tool for understanding the molecular pathomechanisms of peripheral neuropathies;- identification of novel disease-causing genes and mutations implicated in inherited forms of peripheral neuropathies and epilepsies using population and family based genetic approaches.Aminoacyl-tRNA synthetases are ubiquitously expressed and essential proteins, involved in the initial steps of protein biosynthesis and therefore indispensible for cell survival. We recently reported that specific mutations in the tyrosyl-tRNA synthetase (TyrRS, YARS) cause Dominant Intermediate Charcot-Marie-Tooth disease type C (DI-CMTC) - a genetic and phenotypic variant of inherited peripheral neuropathy. It is enigmatic how mutations in this protein can lead to a peculiar specificity of the pathophysiological deficit, characterized by axonal degeneration of the peripheral nerves only. We were the first to establish that the DICMTC phenotype is not due to haploinsufficiency of enzymatic activity, but to a gain-offunction alteration of the mutant YARS or interference with an unknown function of the wild type protein. To unravel the alternative function of YARS in the nervous system we developed the first Drosophila model for inherited peripheral neuropathy, as well as appropriate cellular and yeast systems. We apply a genetic approach of an unbiased, gain-of-function modifier screen to identify genes, whose function modulates neuron-specific mutant YARS phenotypes in fly. The most promising putative modifiers are studied in details using different experimental paradigms. In this way we aim to pinpoint the main molecular pathways where this protein is involved and to simultaneously unravel known or novel molecular pathomechanisms implicated in CMT.In a parallel research direction we tackle the complex molecular pathology of clinically and genetically heterogeneous disorders, like inherited peripheral neuropathies and inherited epilepsies, using the advantages of founder or inbred populations. Our starting material are unique collections of nuclear inbred families with autosomal-recessive CMT forms coming from different geographic regions and ethnic groups of the world, as well as epileptic families belonging to the isolated population of European Gypsies. Using genetic approaches for mapping of recessive disorders combined with the most recent advances in genotyping technologies, we aim to create a powerful tool for disease-causing locus and gene identification. The identification of genes implicated in different forms of peripheral neuropathies and epilepsies contributes to the understanding of the pathophysiology of these disorders by revealing new disease mechanisms or strengthening the importance of the known ones. The mutations that are found allow genotype-phenotype correlations and have an important impact on the diagnostics, genetic counseling and disease prevention. Our findings provide the rational basis for the development of novel drugs and therapeutic concepts.
Keywords:AMINOACYL-TRNA SYNTHETASES, NEURODEGENERATION, INBRED POPULATIONS, MOLECULAR GENETICS, FUNCTIONAL GENOMICS
Disciplines:Genetics, Systems biology, Biomaterials engineering, Biological system engineering, Biomechanical engineering, Other (bio)medical engineering, Environmental engineering and biotechnology, Industrial biotechnology, Other biotechnology, bio-engineering and biosystem engineering, Molecular and cell biology, Psychiatry and psychotherapy, Nursing, Other paramedical sciences, Clinical and counseling psychology, Other psychology and cognitive sciences