RESUMEN
Beta III spectrin is present throughout the elaborate dendritic tree of cerebellar Purkinje cells and is required for normal neuronal morphology and cell survival. Spinocerebellar ataxia type 5 (SCA5) and spectrin associated autosomal recessive cerebellar ataxia type 1 are human neurodegenerative diseases involving progressive gait ataxia and cerebellar atrophy. Both disorders appear to result from loss of ß-III spectrin function. Further elucidation of ß-III spectrin function is therefore needed to understand disease mechanisms and identify potential therapeutic options. Here, we report that ß-III spectrin is essential for the recruitment and maintenance of ankyrin R at the plasma membrane of Purkinje cell dendrites. Two SCA5-associated mutations of ß-III spectrin both reduce ankyrin R levels at the cell membrane. Moreover, a wild-type ß-III spectrin/ankyrin-R complex increases sodium channel levels and activity in cell culture, whereas mutant ß-III spectrin complexes fail to enhance sodium currents. This suggests impaired ability to form stable complexes between the adaptor protein ankyrin R and its interacting partners in the Purkinje cell dendritic tree is a key mechanism by which mutant forms of ß-III spectrin cause ataxia, initially by Purkinje cell dysfunction and exacerbated by subsequent cell death.