Cell, 2003-05, Vol.113 (4), p.457-468
2003
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- Autor(en) / Beteiligte
- Titel
- Interaction of Akt-Phosphorylated Ataxin-1 with 14-3-3 Mediates Neurodegeneration in Spinocerebellar Ataxia Type 1
- Ist Teil von
- Cell, 2003-05, Vol.113 (4), p.457-468
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2003
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/S0092-8674(03)00349-0Titel-ID: cdi_proquest_miscellaneous_18763542
- Format
- –
- Schlagworte
- 14-3-3 Proteins, Amino Acid Motifs - genetics, Amino Acid Sequence - genetics, Animals, Ataxin-1, Ataxins, Cell Nucleus - genetics, Cell Nucleus - metabolism, Cell Nucleus - pathology, COS Cells, Drosophila melanogaster, Drosophila Proteins, 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, Proto-Oncogene Proteins c-akt, Serine - genetics, Serine - metabolism, Spinocerebellar Ataxias - genetics, Spinocerebellar Ataxias - metabolism, Trinucleotide Repeat Expansion - genetics, Tyrosine 3-Monooxygenase - genetics, Tyrosine 3-Monooxygenase - metabolism