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Akt and CHIP coregulate tau degradation through coordinated interactions
Open accessAbstract
A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.
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“AKT phosphorylates and enhances PAR-1 activity (125).”
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Metadata
- Authors
- Dickey, C. A., Koren, J., Zhang, Y.-J., Xu, Y.-F., Jinwal, U. K., Birnbaum, M. J., Monks, B., Sun, M., Cheng, J. Q., Patterson, C., Bailey, R. M., Dunmore, J., Soresh, S., Leon, C., Morgan, D., & Petrucelli, L.
- Affiliations
- University of South Florida (US)
- Mayo Clinic (US)
- Howard Hughes Medical Institute (US)
- University of North Carolina at Chapel Hill (US)
- *Department of Molecular Pharmacology and Physiology and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-03-04
- Volume
- 105
- Issue
- 9
- Pages
- 3622-3627
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2265134
- OpenAlex
- W2075401349
- Cited by
- 226
- References
- 21
- Citations by year
- 2026: 15 · 2025: 11 · 2024: 9 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 8 · 2019: 10 · 2018: 15 · 2017: 15 · 2016: 11 · 2015: 10 · 2014: 18 · 2013: 9 · 2012: 16
- FWCI
- 11.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Alzheimer's Association
- American Federation for Aging Research
- CurePSP
- National Institutes of Health (AG17216)
- National Institute on Aging (K99AG031291, R01-AG17216-08, R00AG031291, P01AG017216, K99-AG31291)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK56886, R01DK056886)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Akt, CHIP, tau degradation, tau phosphorylation, HSP90, ubiquitination, Alzheimer's disease, tau aggregation, protein quality control
- MeSH terms
- Alzheimer Disease, Animals, Phosphorylation, tau Proteins, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, HSP90 Heat-Shock Proteins, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-akt, Mice
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