Neurons expend considerable effort maintaining and sometimes degrading axons in response to a variety of cues. Human genetic phenotypes afforded by diseases characterized by axonal degeneration and study of the corresponding disease genes may shed light into the mechanisms responsible for axonal homeostasis and neurodegenerative disorders. Mutations in Spastin, an AAA ATPase that is widely expressed, are the most common cause of autosomal dominant Hereditary Spastic Paraplegia (HSP), a retrograde axonopathy primarily affecting the corticospinal tracts and the fasciculis gracilis characterized clinically primarily by spastic gait.  HSP has been linked to over thirty loci and several of the disease genes have been identified.

Using biochemical assays and real time video-microscopy we showed that Spastin is a microtubule severing enzyme that capable of making internal breaks in microtubules. We also found that disease associated mutations in Spastin abolish microtubule severing.  We also found that Spastin is stabilized and localized in cells by interacting with Atlastin, another HSP-associated protein. We found a clinical mutation in Atlastin that prevents Spastin interaction. Because we have found Spastin associating with another HSP gene product, we are exploring the hypothesis that mutations in different HSP genes are interfering at various steps in a single cell biological pathway important in axonal maintenance.

We are currently exploring the functions of Spastin in the production and maintenance of axons and dendrites in primary neurons in culture, identifying signaling pathways and molecules that localize Spastin to specific sites of action and regulate its activity, and analyzing Spastin and HSP gene function in vivo in C. elegans.  We are also elucidating the biochemical mechanism utilized by this ATP driven machine in severing microtubules.

Selected Recent Publications:

• Evans, K., Keller, C., Pavur, K., Glasgow, K., Conn, B.,& Lauring, B.(2006). Interaction of two Hereditary Spastic Paraplegia gene products, Spastin and Atlastin, suggests a common pathway for axonal maintenance. Proc. Natl Acad. Sci, USA. 103;10,666-71.
• Evans, K., Gomes, E., Reisenweber, S., Gundersen, G, & Lauring, B. (2005). Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J. Cell Biol. 168:599-606.
• Martinez, J., Moeller, I., Erdjument-Bromage, H., Tempst, P., and Lauring, B. (2003). "Parkinson's disease associated a synuclein is a calmodulin substrate." J Biol Chem 278(19).