title: 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.
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.
authors.affiliation: The Centre for Integrative Physiology and Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK and.
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Clarkson
authors.affiliation: The Centre for Integrative Physiology and Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK and.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Perkins
authors.affiliation: The Centre for Integrative Physiology and.
authors.forename: Callum J
authors.initials: CJ
authors.lastname: Cairncross
authors.affiliation: School of Life Sciences, Heriot-Watt University, John Muir Building, Riccarton, Edinburgh EH14 4AS, UK.
authors.forename: Alastair R
authors.initials: AR
authors.lastname: Lyndon
authors.affiliation: The Centre for Integrative Physiology and Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK and.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Skehel
authors.affiliation: The Centre for Integrative Physiology and Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK and mandy.jackson@ed.ac.uk.
authors.forename: Mandy
authors.initials: M
authors.lastname: Jackson
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D055550:Protein Stability; D011689:Purkinje Cells / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000502:physiology*; D013049:Spectrin / Q000235:genetics* / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics*
chemical_list: D017487:Ankyrins; C000595041:SPTBN2 protein, mouse; D015222:Sodium Channels; D013049:Spectrin