We use Drosophila melanogaster as a model to understand nervous system development and function. In a genetic screen for molecules important to these processes, we discovered the fly ortholog of the spastin gene, which when mutated in humans leads to a progressive neurodegenerative disease called Autosomal-Dominant Hereditary Spastic Paraplegia (AD-HSP). Individuals with AD-HSP have difficulty walking, sometimes from as early as childhood, and often end up confined to wheelchairs. We have shown that loss of spastin in the fly larva compromises motoneuron function, while adults exhibit weak legs and do not fly. Spastin is a member of the AAA family of ATPases, and functions by severing microtubules into smaller segments. This form of regulation has been shown for only one other protein, katanin, which is closely related to spastin. Our results indicate that the absence of such microtubule severing in spastin mutant flies leads to a reduction in microtubule content at synaptic boutons, presumably causing the weakened neurotransmission. Among our goals in the lab are thus to understand how this happens at a cell-biological level, and to examine specific phenotypes associated with mutations mimicking those found in the human disease. Using Drosophila as a model system allows us to rapidly generate flies with any number of specific spastin mutations, and then study the consequences of these mutations at the biochemical, cell biological, developmental, electrophysiological and behavioral levels.
Areas of Interest:
The role of microtubule severing in the nervous system
Regulation of microtubule severing proteins
Drosophila models of human disease such as AD-HSP
Molecular mechanisms of synapse formation
Current projects: Analysis of Drosophila models of human AD-HSP, Genetic screen for candidate interactors of spastin, kat60, or kat-like, Cell biology of microtubule regulation by Spastin and other AAA ATPases, Characterization of Spastin function in other fly tissues/stages, Role of microtubule severing in synaptic bouton formation