Molecular mechanisms of β-iii-spectrin in dendritic arborization and spinocerebellar ataxia type 5

Abstract

β-III-spectrin is a membrane-associated cytoskeletal protein predominantly expressed in the cerebellum, and is essential for the maintenance and development of the complex dendritic arbors extended by Purkinje neurons. Mutations in various functional domains of β-III-spectrin cause the neurodegenerative disease spinocerebellar ataxia type 5 (SCA5). My dissertation has focused on understanding the molecular mechanisms by which β-III-spectrin supports neuronal structure and function and how SCA5 mutations disrupt this function. Specifically, my work has shown that the β-III-spectrin N-terminal domain, preceding the actin-binding domain, is required for SCA5-induced high-affinity actin binding and arborization defects in vivo. Furthermore, through characterizing the molecular consequences of SCA5 mutations in the spectrin-repeat domains (SRDs) of β-III-spectrin, I have shown that SRD2- and SRD3-localized mutations disrupt the physical interaction of β-III-spectrin with actin and α-II-spectrin. My dissertation work has provided significant insights into the role of β-III-spectrin in the actin cytoskeleton and the mechanisms underlying SCA5, laying the groundwork for developing a drug compound to treat this currently untreatable disease.