DROSOPHILA ATLASTIN, EFHC1 AND MITOFUSIN HOMOLOGS: FUNCTIONAL INSIGHTS AND GENERATION OF NEW DISEASE MODELS

The ultimate goal of this research is to generate new animal models that will allow the elucidate the pathological mechanisms underlying three neurological disorders: a form of Hereditary Spatic Paraplegia associated to mutation of the gene encoding atlastin (SPG3A), Juvenile Myoclonic Epilepsy linked to the EFHC1 gene and Charcot-Marie-Tooth type 2A, a peripheral neuropathy caused by mutations in the mitofusin 2 gene. Currently models for these diseases in mammalian systems are not available or their development is particularly challenging, Therefore we will use Drosophila melanogaster (the common fruit fly), experimentally a much simpler organism, as a model to investigate the pathogenetic mechanisms underlying these diseases. This approach is possible because the Drosophila genome contains genes that share extensive structural homology with atlastin, EFHC1 and mitofusin 2, and historically a remarkable functional conservation between such closely related human and fly genes has allowed to extend the results obtained in Drosophila to human biology. Moreover, it has been shown that when fly genes with similarity to specific human disease genes are disrupted, and pathological mutant forms of these fly proteins or their mammalian counterparts are transgenically introduced in Drosophila, the resulting phenotypes often display distinctive features of the corresponding human pathologies. We have generated a series of molecular and genetic tools that will be used to generate these disease models. “diseased” flies together with the variety of experimental approaches available in Drosophila likely will improve substantially our understanding of the pathogenesis of Hereditary Spatic Paraplegia, Juvenile Myoclonic Epilepsy and Charcot-Marie-Tooth type 2A, and will open the way to novel therapeutic approaches.