A DROSOPHILA MODEL FOR HUMAN NEURODEGENERATIVE DISEASES. FUNCTIONAL ANALYSIS OF THE TORSIN, SURF1 AND SPASTIN FLY HOMOLOGS

The goal of this proposal is to elucidate the function of three novel genes implicated in human neurodegenerative diseases. Torsin is the gene responsible for early-onset torsion dystonia; the SURF1 gene has been shown to be mutated in an autosomal form of Leigh syndrome and the gene encoding spastin has been associated with the most common form of dominant hereditary spastic paraplegia. Since the function of these human genes is unknown and their analysis in mammalian systems can be extremely challenging, I will use Drosophila (the fruit fly), experimentally a much simpler organism, as a model to investigate their physiological role. The extensive structural and functional conservation between human and fly genes will allow us to extend the results obtained with these studies, to human biology. I have identified, isolated and cloned the fly homologs of torsin, surf1 and spastin, and I will use the molecular and genetic tools available in Drosophila to carry out gene function studies. Experimental disruption and/or overactivation of these genes in Drosophila, will result in readily observable phenotypes. The detailed analysis of these phenotypes will allow to make predictions as to the roles these genes normally play in the organism. A better comprehension of the normal function of these genes will help us to elucidate the molecular mechanisms of neurodegeneration that are presently little understood. Recent work by other investigators has demonstrated that when fly genes with similarity to specific human disease genes are disrupted, and mutant forms of the fly proteins or their mammalian counterparts are artificially introduced in Drosophila, the resulting phenotypes often display key features of the corresponding human pathologies. Therefore, the fly is an excellent model to investigate disease gene function. A deeper understanding of the function of these genes will shed light on the pathogenetic mechanisms underlying disease onset and progression.