Models of atlastin function and dysfunction

The ultimate goal of this research is to understand the pathophysiology of a form of Hereditary Spastic Paraplegia (HSP) associated to mutation of the gene encoding atlastin (SPG3A) and generate new models that will allow to elucidate the mechanisms underlying this neurological disorder. In this project we will study both Drosophila atlastin, whose function we have recently identified, and human atlastins to better understand their precise role within the cell. A combination of experimental approaches will be applied in the course of these studies. We will perform structural studies because they will permit to shed more light on how the atlastin protein works and establish how pathological mutations identified in HSP patients can modify the structure and consequently the function of atlastin. We will identify proteins that can regulate the activity of atlastin to place atlastin in the context of a functional cellular network. Moreover mutation of these regulatory proteins in humans could be responsible for the pathogenesis of other forms of HSP or related motor neuron diseases. Finally, we aim to create disease models using Drosophila melanogaster (the common fruit fly) because it is an experimentally much simpler organism. The generation of a disease model, which is currently not available, will be of the utmost importance to examine the cellular basis of atlastin dysfunction and to test drugs for the treatment of HSP. The proposed studies will greatly benefit from the experimental tools and expertise we have acquired during the investigation of Drosophila atlastin and will substantially improve our understanding of the pathogenesis of Hereditary Spatic Paraplegia potentially opening the way to the development of novel therapeutic approaches.