Role of spectin mutations in Spinocerebellar Ataxias

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DESCRIPTION (provided by applicant): Our lab has discovered that ¿-III spectrin (SPTBN2] mutations cause spinocerebellar ataxia type 5 (SCA5), in three reported affected families. The American and the French SCA5 families have separate in-frame deletions of 39 and 15 bp, respectively, in the third spectrin repeat. These changes are likely to disrupt the organization of the tetrameric alpha-beta spectrin complex. A third mutation, found in a German family, is located in the ARP1 binding region of ¿-III spectrin, which, if functional, could cause generalized dysfunction of dynein-dynactin mediated protein transport. Spectrin mutations are a novel cause of ataxia, a neurodegenerative disease that may affect glutamate signaling, as well as vesicle trafficking, pathways previously implicated in Alzheimer and Huntington diseases, SCA1 (Spinocerebellar Ataxia 1) and ALS (Amyotrophic Lateral Schlerosis). Furthermore, there are extensive reports of mutations in ¿-III spectrin homologues causing movement disorders in other species. To assess whether the SCA5 mutations can affect vesicle-mediated protein transport and cause neurodegeneration, we have generated and begun to characterize a Fly model of SCA5. Human ¿-III spectrin either wild type or carrying the SCA5 mutations is being expressed in neurons, ovaries and different fly tissues using the GAL4-UAS expression system. Our experimental strategy is also designed to uncover other functions of ¿-spectrins that might turn out to be mechanistically relevant in ataxia. To gain a deeper understanding of the role of spectrin proteins in ataxia and the molecular consequences of the SCA5 mutations, we are screening a DNA bank of ataxia patients for additional mutations in SPTBN2 as well as mutations in the spectrin beta-non erythrocyte 5 gene (SPTBN5). This research can result in the discovery and better understanding of the causes and mechanisms of pathogenesis of some types of ataxia, a group of genetic diseases that affect the nervous systems in humans. The discovery of the causes of ataxia would offer tools for the direct and unambiguous diagnosis of the disease. Additionally, an understanding of the causes of the disease at the biochemical level would be valuable input in the design of drugs or other therapies for its treatment in the future.