Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA
Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA
Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA
Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA
Institute of Human Genetics, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455 USA
Department of Biology and Program in Genetics, Texas A&M University, College Station, TX 77843 USA
Institute of Molecular Biology and Genetics, BSRC ÒA. FlemingÓ, 16672 Vari, Greece
Division of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, Edinburgh, EH8 9XD, Scotland United Kingdom
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.