Role of spectrin mutations in spinocerebellar ataxia type five (SCA5)

Abstract

Spinocerebellar ataxia type 5 (SCA5) is a dominant neurodegenerative disorder caused by mutations in the SPBTN2 gene encoding the cytoskeletal protein beta-III spectrin. To get insight into the biology of the disease and the normal function of beta-III spectrin, and to estimate the frequency of SCA5 mutations among ataxia patients, I used a forward human genetic approach to identify novel SPTBN2 mutations. Screening of the SPTBN2 gene in a cohort of families with dominant ataxia of unknown etiology and a large group of ataxia samples identified seventeen novel variants not found in the general population. Putative mutations were identified in the areas comprising the second calponin homology domain, spectrin repeat two to four, and the ninth spectrin repeat of beta-III spectrin. To investigate the downstream effects of the American and German SCA5 mutations in neurons, I established a series of transgenic Drosophila models that express human beta-III-spectrin or fly beta-spectrin proteins containing SCA5 mutations. Through genetic and functional analyses I show that expression of mutant spectrin in the eye causes a progressive neurodegenerative phenotype and expression in larval neurons results in posterior paralysis, reduced synaptic terminal growth, and axonal transport deficits. These phenotypes are genetically enhanced by both dynein and dynactin loss-of-function mutations. I have additionally used the SCA5 fly models to conduct modifier screens and identify genes and biological pathways that may contribute to SCA5 pathogenesis. These studies revealed genetic interactors implicated in a wide range of biological functions including intracellular transport, synapse formation and function, protein homeostasis, and transcription regulation.