The hereditary spastic paraplegias (HSPs) are a set of diseases in which longer spinal cord axons degenerate. The pathological mechanisms of degeneration in HSPs are poorly understood, even in cases when causative genes have been cloned. To date, some thirty causative loci (SPG loci) have been mapped and thirteen cloned. The host laboratory has recently identified a mechanism by which one gene product, SPG6, can affect axonal transport. The Drosophila SPG6 homolog, spichthyin, is a novel antagonist of BMP/TGF-beta signaling that acts by modulating receptor traffic. Furthermore, the host lab has found that BMP signaling is required for maintenance of axonal microtubules (MTs) in Drosophila, and that impairment of this signaling leads to loss of axonal MTs and impairment of axonal transport. This role of BMP signaling is a novel cellular process, and may be a target for other degenerative diseases. The purpose of the project is to determine how BMP signaling regulates axonal MTs. The specific objectives are (i) to determine if BMP regulation of MTs acts via the canonical BMP pathway that involves transcriptional regulation, and/or via a more localised non-canonical pathway; (ii) to test if the MT regulation occurs by regulation of tubulin expression, and/or by activity of of MT-binding proteins; (iii) to use live imaging and techniques such as FRAP to study the effect of BMP signaling on dynamic localization and traffic of MTs. The identification of such mechanisms will allow a better understanding of both BMP signaling and MT regulation in both healthy and disease states. This project is original and innovative in that it builds on recent pioneering work in the host lab that links an important neuronal signaling pathway with basic processes of axonal MT regulation and transport. Study of the target pathway of SPG6 is timely because it can provide a framework of knowledge to understand the mechanisms of degeneration in other axonal degeneration diseases.
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