Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1

Hung Kai Chen, Pedro Fernandez-Funez, Summer F. Acevedo, Yung C. Lam, Michael D. Kaytor, Michael H. Fernandez, Alastair Aitken, Efthimios M C Skoulakis, Harry T. Orr, Juan Botas, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

330 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)457-468
Number of pages12
JournalCell
Volume113
Issue number4
DOIs
StatePublished - May 16 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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