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.