Cited by 226Alzheimer's disease research and treatmentsHeat shock proteins researchUbiquitin and proteasome pathways

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Akt and CHIP coregulate tau degradation through coordinated interactions

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Dickey, Chad A., Koren, John, Zhang, Yong-Jie, Xu, Ya-fei, Jinwal, Umesh K., Birnbaum, Morris J., Monks, Bobby, Sun, Mei, Cheng, Jin Q., Patterson, Cam, Bailey, Rachel M., Dunmore, Judith, Soresh, Sareh, Leon, Carlos, Morgan, Dave, Petrucelli, Leonard·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0709180105PMC PMC2265134

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Abstract

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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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: Dickey, Chad A.
Koren, John
Zhang, Yong-Jie
Birnbaum, Morris J.
Sun, Mei
Cheng, Jin Q.
Bailey, Rachel M.
Petrucelli, Leonard
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
DOI: 10.1073/pnas.0709180105
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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Akt and CHIP coregulate tau degradation through coordinated interactions

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