Murine models of spinocerebellar ataxia type 5

Abstract

Spinocerebellar ataxia type 5 (SCA5) is a slowly progressive neurodegenerative disease of the cerebellum caused by mutations in the SPTBN2 gene, which encodes the protein β-III spectrin. To characterize how β-III spectrin with the American SCA5 mutation causes Purkinje cell degeneration and cerebellar dysfunction, I developed the first transgenic murine models of SCA5 and identified brain proteins that potentially interact with the region of β-III spectrin where the American SCA5 mutation occurs. Behavioral studies with a conditional model that drives expression of untagged β-III spectrin and a second 3xFLAG-tagged SCA5 model show that overexpressing mutant β- III spectrin in murine cerebellar Purkinje cells causes cerebellar dysfunction. Further studies with the conditional tet-regulated mice show that untagged mutant β-III spectrin alters the localization of the glutamate transporter EAAT4 and the metabotropic glutamate receptor mGluR1α and produces a concomitant deficit in mGluR1 function. Histologic analysis of the 3xFLAG-tagged SCA5 murine model shows that the American SCA5 mutation also alters the Purkinje cell distribution of the mutant β-III spectrin protein itself. Additionally, I identified a number of brain proteins that are novel β-III spectrin interaction candidates, including the dynactin subunit p150Glued. I show that the American and French SCA5 mutations alter the interaction strength of β-III spectrin with p150Glued and α-II spectrin respectively.