Objective The hereditary spastic paraplegias (HSPs) are a group of neurodegenerative conditions characterised by the degeneration of longer spinal cord motor tract axons. The normal function of the 13 cloned spastic paraplegia genes (SPGs) is largely unknown, but most encode intracellular membrane-associated proteins. Recently, the host laboratory has established that one of these genes, SPG6, encodes an endosomal regulator of BMP receptor trafficking, and regulates synaptic growth and axonal microtubules via this effect. The aim of this project is to test whether other intracellular membrane SPG products also function in receptor membrane trafficking and signalling, particularly in the BMP pathway. The focus of the study will be on the three SPGs currently most amenable to study in Drosophila melanogaster, a model system with proven power in this area. Top priority will be given to the recently identified spastizin (SPG15), an endosomal localised protein containing a FYVE motif, found on proteins that function in the regulation of endocytic trafficking. Mutants of the Drosophila SPG15 homologue will be generated to study phenotypes, particularly at the neuromuscular junction (NMJ). Also, antibodies will be generated to investigate spastizin colocalisation and association with BMP, Wnt, and Notch pathway subunits. In addition, I will use similar approaches to test two other membrane associated SPG products: spastin (SPG4) and atlastin (SPG3A). These are among the most commonly mutated SPGs, thus Drosophila stocks and reagents are already available, but their potential role in regulating endosomal trafficking pathways is not well studied. This investigation, into the functional pathways of spastizin, spastin, and atlastin, will further the understanding of the mechanism of action of mutated proteins in motor neuron degeneration. Fields of science natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteins Keywords Cell biology Degenerative diseases Genetics Molecular genetics Neurobiology Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-IEF-2008 - Marie Curie Action: "Intra-European Fellowships for Career Development" Call for proposal FP7-PEOPLE-IEF-2008 See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE EU contribution € 170 733,61 Address TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge United Kingdom See on map Region East of England East Anglia Cambridgeshire CC Activity type Higher or Secondary Education Establishments Administrative Contact Edna Murphy (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
