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

360 Scopus citations


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
Issue number4
StatePublished - May 16 2003

Bibliographical note

Funding Information:
We thank Dr. R.G. Cook for mass spectrometry analysis, R. Atkinson for confocal microscopy, Karthik Chirala for technical assistance, K.W. Choi and K.O. Choi for assistance with eye sections, and V. Brandt for tightening the manuscript. This research was supported by the NIH with grants to H.Y.Z. (NS27699), J.B. (NS42179), H.T.O. (NS22920), and by MRRC Cores at Baylor (HD24064). H.Y.Z. is an Investigator and H.-K.C. is a Postdoctoral Research Associate with HHMI. P.F.-F. is a Postdoctoral Fellow supported by the Hereditary Disease Foundation.


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