Molecular cell biology and pathology of hereditary spastic paraplegia. (360G-Wellcome-082381_Z_07_Z)

Our overall goal is to understand better the molecular processes involved in axonal maintenance and degeneration. We will do this by studying the hereditary spastic paraplegias (HSPs), genetic conditions in which long axons in the spinal cord degenerate. We will analyse the normal and pathological functions of two HSP proteins that we have identified as binding-partners, spastin and atlastin. These proteins are involved in processes at the interface between membrane traffic and microtubule re gulation. We will examine functional assays for selected membrane traffic pathways in cell models of spastin- and atlastin- HSP. We will explore a potential mechanism by which abnormal traffic in these pathways may cause axonal degeneration, by analysing whether defects in axonal transport of cargoes derived from them are an early feature in cellular models of spastin- and atlastin-HSP. In the light of our preliminary work suggesting its importance in one type of HSP, we will determine whether abnormalities in BMP signalling are a unifying pathological feature of a group of HSPs, including spastin- and atlastin- HSP. Finally, we will use yeast-two hybrid screening as a basis to identify unrecognised HSP protein interactions, to extend the HSP protein interaction network and to identify new HSP candidate genes.