Toxicity and endocytosis of spinocerebellar ataxia type 6 polyglutamine domains: Role of myosin IIB - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Traffic Année : 2008

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

Beatrice Marqueze-Pouey
  • Fonction : Auteur
Nicole Martin-Moutot
  • Fonction : Auteur
Marie Sakkou-Norton
  • Fonction : Auteur
Yong Ji
  • Fonction : Auteur
Wendy L. Hsiao
  • Fonction : Auteur
Michael Seagar
  • Fonction : Auteur

Résumé

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 Ca(v)2.1 C-terminal domains expressed in the plasma membrane. In COS-7 cells, CD4-green fluorescent protein fused to Ca(v)2.1 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 Ca(v)2.1 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 S-35-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 Ca(v)2.1Ct at the plasma membrane and suggest that this gain of function might contribute to the pathogenesis of SCA6.
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Dates et versions

hal-00709920 , version 1 (19-06-2012)

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Beatrice Marqueze-Pouey, Nicole Martin-Moutot, Marie Sakkou-Norton, Christian Leveque, Yong Ji, et al.. Toxicity and endocytosis of spinocerebellar ataxia type 6 polyglutamine domains: Role of myosin IIB. Traffic, 2008, 9 (7), pp.1088-1100. ⟨10.1111/j.1600-0854.2008.00743.x⟩. ⟨hal-00709920⟩
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