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

Cell. 2003 May 16;113(4):457-68. doi: 10.1016/s0092-8674(03)00349-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 14-3-3 Proteins
  • Amino Acid Motifs / genetics
  • Amino Acid Sequence / genetics
  • Animals
  • Ataxin-1
  • Ataxins
  • COS Cells
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Drosophila Proteins
  • Drosophila melanogaster
  • Humans
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Models, Biological
  • Mutation / genetics
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptides / genetics
  • Peptides / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Binding / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Serine / genetics
  • Serine / metabolism
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / metabolism*
  • Trinucleotide Repeat Expansion / genetics
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism*

Substances

  • 14-3-3 Proteins
  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Drosophila Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Proto-Oncogene Proteins
  • polyglutamine
  • Serine
  • Tyrosine 3-Monooxygenase
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Akt1 protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt