Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The TTC3 gene is involved in the regulation of AKT signaling and is related with immune tolerance and neuronal cell survival.
“Furthermore, the TTC3 gene is also involved in the regulation of AKT signaling and is related with immune tolerance and neuronal cell survival (Chen et al., 2003; Liu et al., 2009; Pulst, 2016).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Chen et al., 2003
Activated AKT is a mediator of neuronal cell survival.
“In addition, activated AKT is a mediator of neuronal cell survival (Liu et al., 2002; Chen et al., 2003; Pulst, 2016).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Chen et al., 2003
The citation lists haven’t been fetched yet
References 35 · Cited by 414
- Authors
- Chen, H.-K., Fernandez-Funez, P., Acevedo, S. F., Lam, Y. C., Kaytor, M. D., Fernandez, M. H., Aitken, A., Skoulakis, E. M. C., Orr, H. T., Botas, J., & Zoghbi, H. Y.
- Affiliations
- Howard Hughes Medical Institute (US)
- Texas A&M University (US)
- Baylor College of Medicine (US)
- University of Minnesota (US)
- University of Edinburgh (GB)
- Alexander Fleming Biomedical Sciences Research Center (GR)
- Corresponding author
- Zoghbi, Huda Y.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 113
- Issue
- 4
- Pages
- 457-468
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1998879017
- Cited by
- 414
- References
- 35
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 8 · 2018: 7 · 2017: 6 · 2016: 8 · 2015: 9 · 2014: 18 · 2013: 20 · 2012: 19
- FWCI
- 15.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS 27699, NS42179, NS-22920)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 24064, P30HD024064)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Keywords
- spinocerebellar ataxia type 1, ataxin-1, 14-3-3 proteins, Akt phosphorylation, polyglutamine, CAG repeat expansion, neurodegeneration, protein stabilization, protein degradation, phosphatidylinositol 3-kinase/Akt signaling, Drosophila model, therapeutic target
- MeSH terms
- Ataxins, Ataxin-1, Amino Acid Sequence, Animals, Cell Nucleus, Inclusion Bodies, Drosophila melanogaster, Humans, Models, Biological, Mutation, Nerve Degeneration, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Serine, Tyrosine 3-Monooxygenase, Protein Serine-Threonine Kinases, COS Cells, Trinucleotide Repeat Expansion, Phosphatidylinositol 3-Kinases, Spinocerebellar Ataxias, Amino Acid Motifs, Drosophila Proteins, 14-3-3 Proteins, Proto-Oncogene Proteins c-akt
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
