β-III spectrin underpins 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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-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 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
Pages (from-to)3875-3882
Number of pages8
JournalHuman Molecular Genetics
Volume23
Issue number14
Early online date6 Mar 2014
DOIs
Publication statusPublished - 15 Jul 2014

Keywords

  • AXON INITIAL SEGMENTS
  • ATAXIA TYPE 5
  • HEREDITARY SPHEROCYTOSIS
  • MEMBRANE SKELETON
  • IV-SPECTRIN
  • RANVIER
  • BINDING
  • NODES
  • MONOLAYER
  • ISOFORMS

Fingerprint Dive into the research topics of 'β-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: Protein complex critical for sodium channel activity is impaired by SCA5-associated mutations'. Together they form a unique fingerprint.

Cite this