β-III spectrinunderpins ankyrin R function in purkinje cell dendritic trees: Protein complex critical for sodium channel activity is impaired by SCA5-associated mutations

Yvonne L. Clarkson, Emma M. Perkins, Callum J. Cairncross, Alastair R. Lyndon, Paul A. Skehel, Mandy Jackson

    Research output: Contribution to journalArticlepeer-review

    20 Citations (Scopus)

    Abstract

    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 β-III spectrin function. Further elucidation of β-III spectrin function is therefore needed to understand disease mechanisms and identify potential therapeutic options. Here, we report that β spectrin is essential for the recruitment and maintenance of ankyrin R at the plasma membrane of Purkinje cell dendrites. Two SCA5-associated mutations of β-III spectrin both reduce ankyrin R levels at the cell membrane. Moreover, a wild-type β-III spectrin/ankyrin-R complex increases sodium channel levels and activity in cell culture, whereas mutant β-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 β-III spectrin cause ataxia, initially by Purkinje cell dysfunction and exacerbated by subsequent cell death.

    Original languageEnglish
    Article numberddu103
    Pages (from-to)3875-3882
    Number of pages8
    JournalHuman Molecular Genetics
    Volume23
    Issue number14
    DOIs
    Publication statusPublished - 1 Jan 2014

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)
    • Molecular Biology

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