First Author | Clarkson YL | Year | 2014 |
Journal | Hum Mol Genet | Volume | 23 |
Issue | 14 | Pages | 3875-82 |
PubMed ID | 24603075 | Mgi Jnum | J:210998 |
Mgi Id | MGI:5573010 | Doi | 10.1093/hmg/ddu103 |
Citation | Clarkson YL, et al. (2014) beta-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: protein complex critical for sodium channel activity is impaired by SCA5-associated mutations. Hum Mol Genet 23(14):3875-82 |
abstractText | 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 beta-III spectrin function. Further elucidation of beta-III spectrin function is therefore needed to understand disease mechanisms and identify potential therapeutic options. Here, we report that beta-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 beta-III spectrin both reduce ankyrin R levels at the cell membrane. Moreover, a wild-type beta-III spectrin/ankyrin-R complex increases sodium channel levels and activity in cell culture, whereas mutant beta-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 beta-III spectrin cause ataxia, initially by Purkinje cell dysfunction and exacerbated by subsequent cell death. |