Toxicity and endocytosis of spinocerebellar ataxia type 6 polyglutamine domains: Role of myosin IIB†

Béatrice Marquèze-Pouey*, Nicole Martin-Moutot, Marie Sakkou-Norton, Christian Lévêque, Yong Ji, Véronique Cornet, Wendy W L Hsiao, Michael Seagar

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

15 Citations (Scopus)


Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease caused by a small expansion of CAG repeats in the sequence coding for the cytoplasmic C-terminal region of the Ca v 2.1 subunit of P/Q-type calcium channels. We have tested the toxicity of mutated Cav2.1 C-terminal domains expressed in the plasma membrane. In COS-7 cells, CD4-green fluorescent protein fused to Cav2.1 C-terminal domains containing expanded 24 polyglutamine (Q) tracts displayed increased toxicity and stronger expression at the cell surface relative to 'normal' 12 Q tracts, partially because of reduced endocytosis. Glutathione S-transferase pull-down and proteomic analysis indicated that Cav2.1 C-termini interact with the heavy and light chains of cerebellar myosin IIB, a molecular motor protein. This interaction was confirmed by coimmunoprecipitation from rat cerebellum and COS-7 cells and shown to be direct by binding of in vitro-translated 35 S-myosin IIB heavy chain. In COS-7 cells, incremented polyglutamine tract length increased the interaction with myosin IIB. Furthermore, the myosin II inhibitor blebbistatin reversed the effects of polyglutamine expansion on plasma membrane expression. Our findings suggest a key role of myosin IIB in promoting accumulation of mutant Cav2.1Ct at the plasma membrane and suggest that this gain of function might contribute to the pathogenesis of SCA6.

Original languageEnglish
Pages (from-to)1088-1100
Number of pages13
Issue number7
Publication statusPublished - Jul 2008

Scopus Subject Areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

User-Defined Keywords

  • CAG repeat
  • Calcium channels
  • Cell toxicity
  • Myosin
  • Neurodegenerative disease
  • Spinocerebellar ataxia


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