The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules
Open accessAbstract
Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulation of proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Our previous work demonstrated that age-related changes to the cellular chaperone repertoire contributes to abnormal buildup of the microtubule-associated protein tau that accumulates in a group of diseases termed tauopathies, the most common being Alzheimer's disease. Here, we show that the Hsp90 cochaperone, FK506-binding protein 51 (FKBP51), which possesses both an Hsp90-interacting tetratricopeptide domain and a peptidyl-prolyl cis-trans isomerase (PPIase) domain, prevents tau clearance and regulates its phosphorylation status. Regulation of the latter is dependent on the PPIase activity of FKBP51. FKB51 enhances the association of tau with Hsp90, but the FKBP51/tau interaction is not dependent on Hsp90.In vitro FKBP51 stabilizes microtubules with tau in a reaction depending on the PPIase activity of FKBP51. Based on these new findings, we propose that FKBP51 can use the Hsp90 complex to isomerize tau, altering its phosphorylation pattern and stabilizing microtubules.
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The Hsp90:FKBP51 system acts in tau proteostasis, raising tau stability and changing its phosphorylation.
“Hsp90:FKBP51 functions in tau proteostasis, increasing its stability and altering phosphorylation states”
From The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state (2021) · cites this paper as Jinwal et al., 2010
Largely mediated via the FK1 domains, FKBP51 and FKBP52 also act as antagonists in regulating the phosphorylation state of the tau protein and its proper recycling.
“Largely mediated via the FK1 domains, FKBP51 and FKBP52 also act as antagonists in regulating the phosphorylation state of the tau protein and its proper recycling [18,19].”
From Differential conformational dynamics in the closely homologous FK506-binding domains of FKBP51 and FKBP52 (2014) · cites this paper as [18]
One or more cochaperones could be more specific drug targets with fewer adverse consequences.
“Recent data suggest that one or more of these cochaperones could be more specific drug targets with fewer adverse consequences [39, 93].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [39]
FKBP51 preserves tau levels but reduces its phosphorylation, perhaps by cooperating with a set of phosphatases.
“Recently, FKBP51 was shown to preserve tau levels, but reduce its phosphorylation, perhaps by cooperating with a set of phosphatases [39].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [39]
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- Authors
- Jinwal, U. K., Koren, J., Borysov, S. I., Schmid, A. B., Abisambra, J. F., Blair, L. J., Johnson, A. G., Jones, J. R., Shults, C. L., O'Leary, J. C., Jin, Y., Buchner, J., Cox, M. B., & Dickey, C. A.
- Affiliations
- University of South Florida (US)
- The University of Texas at El Paso (US)
- Technical University of Munich (DE)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-01-13
- Volume
- 30
- Issue
- 2
- Pages
- 591-599
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2830818
- OpenAlex
- W2084436053
- Cited by
- 214
- References
- 36
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 10 · 2023: 13 · 2022: 5 · 2021: 10 · 2020: 6 · 2019: 14 · 2018: 9 · 2017: 13 · 2016: 14 · 2015: 20 · 2014: 12 · 2013: 18 · 2012: 13
- FWCI
- 13.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- CurePSP
- Rosalinde and Arthur Gilbert Foundation
- Elitenetzwerk Bayern
- National Institute on Aging (R00AG031291)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- FKBP51, Hsp90 co-chaperone, tau protein, tau phosphorylation, microtubule stabilization, peptidyl-prolyl isomerase, tauopathy, Alzheimer's disease, protein aggregation, aging, molecular chaperones, tetratricopeptide repeat domain
- MeSH terms
- Tacrolimus Binding Protein 5, Animals, Brain, Cell Line, Transformed, Chymotrypsin, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Microtubules, Mutation, Oocytes, Transfection, Xenopus, Benzoquinones, tau Proteins, HSP90 Heat-Shock Proteins, Peptidylprolyl Isomerase, Tacrolimus Binding Proteins, RNA, Small Interfering, Lactams, Macrocyclic, Mice
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