I am interested in understanding the molecular mechanisms that control morphogenesis and maintenance of neuronal structures, and how these mechanisms are disrupted to cause neurological disorders. My lab employs protein biochemical techniques, together with genetic and live cell imaging approaches using the model organism Drosophila melanogaster. Students in my lab have the unique opportunity to explore questions in neurobiology at both the single molecule and whole organism level.
A focus of my lab is to understand how the cytoskeleton supports the unique morphologies adopted by neurons. Neuronal morphology is intimately tied to proper functioning of the nervous system. In particular we are currently studying the mechanisms by which the spectrin-actin cytoskeleton supports neuron form and function, and how the spectrin cytoskeleton is disrupted in disease. Mutations in β-III-spectrin cause the neurodegenerative disease, spinocerebellar ataxia type 5 (SCA5). In prior biochemical studies we found that a SCA5 mutation causes β-III-spectrin to binds actin with a striking 1000-fold increased affinity. This high-affinity interaction enabled generation of a cryo-EM structure of mutant β-III-spectrin bound to an actin filament. This structure led to the discovery of a novel motif, an N-terminal helix, required for spectrin actin-binding activity. This cryo-EM structure also confirmed our model that high-affinity actin binding by mutant spectrin results from a specific conformational change within the actin-binding domain of spectrin.
The target neuron in SCA5 pathogenesis is the cerebellar Purkinje cell, which extends a large and highly branched dendritic arbor. To gain insight into how SCA5 mutations impact the dendritic arbors extended by human cerebellar Purkinje cells, we developed an SCA5 model using the fruit fly Drosophila melanogaster. Drosophila sensory neurons expressing SCA5 mutant β-spectrin exhibit a pronounced arbor phenotype. The reduced size of the SCA5 arbor reflects both a degenerative defect, in which distal dendrites are lost, and a developmental defect, in which arbor outgrowth is restricted. Our data suggest the spectrin-actin cytoskeleton functions in neurons to stabilize dendrites and support arbor outgrowth.
