Author/Authors :
Hung-Kai Chen، نويسنده , , Pedro Fernandez-Funez، نويسنده , , Summer F. Acevedo، نويسنده , , Yung C. Lam، نويسنده , , Michael D. Kaytor، نويسنده , , Michael H. Fernandez، نويسنده , , Alastair Aitken، نويسنده , , Efthimios M.C. Skoulakis، نويسنده , , Harry T. Orr، نويسنده , , Juan Botas، نويسنده , , Huda Y. Zoghbi، نويسنده ,
Abstract :
Spinocerebellar ataxia type 1 (SCA1) is one of several neurological disorders caused by a CAG repeat expansion. In SCA1, this expansion produces an abnormally long polyglutamine tract in the protein ataxin-1. Mutant polyglutamine proteins accumulate in neurons, inducing neurodegeneration, but the mechanism underlying this accumulation has been unclear. We have discovered that the 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. The association of ataxin-1 with 14-3-3 is regulated by Akt phosphorylation, and in a Drosophila model of SCA1, both 14-3-3 and Akt modulate neurodegeneration. Our finding that phosphatidylinositol 3-kinase/Akt signaling and 14-3-3 cooperate to modulate the neurotoxicity of ataxin-1 provides insight into SCA1 pathogenesis and identifies potential targets for therapeutic intervention.
