An acetylation–phosphorylation switch that regulates tau aggregation propensity and function
Open accessAbstract
The aberrant accumulation of tau protein is a pathological hallmark of a class of neurodegenerative diseases known as tauopathies, including Alzheimer's disease and related dementias. On the basis of previous observations that tau is a direct substrate of histone deacetylase 6 (HDAC6), we sought to map all HDAC6-responsive sites in tau and determine how acetylation in a site-specific manner affects tau's biophysical properties in vitro . Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. To determine the functional consequence of this HDAC6-regulated phosphorylation event, we examined tau's ability to promote microtubule assembly and found that phosphorylation of Ser-324 interferes with the normal microtubule-stabilizing function of tau. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324–positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation–phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function. Because the disease relevance of this finding is evident, additional studies are needed to examine the role of pSer-324 in tau pathobiology and to determine whether therapeutically modulating this acetylation–phosphorylation switch affects disease progression in vivo .
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Increased Tau acetylation reduces Tau phosphorylation.
“while increased Tau acetylation reduces Tau phosphorylation [34, 42].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [42]
The Discussion reports that acetylation of tau at Lys-321 inhibits phosphorylation at Ser-324. The citing sentence omits those site-specific limits and implies that increased tau acetylation reduces tau phosphorylation generally, which this paper does not establish. (LLM, conf=0.86)
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- Authors
- Carlomagno, Y., Chung, D.-E. C., Yue, M., Castanedes-Casey, M., Madden, B. J., Dunmore, J., Tong, J., DeTure, M., Dickson, D. W., Petrucelli, L., & Cook, C.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Petrucelli, Leonard
- Cook, Casey
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 292
- Issue
- 37
- Pages
- 15277-15286
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5602388
- OpenAlex
- W2741056309
- Cited by
- 143
- References
- 36
- Citations by year
- 2026: 19 · 2025: 14 · 2024: 14 · 2023: 8 · 2022: 11 · 2021: 24 · 2020: 17 · 2019: 19 · 2018: 17
- FWCI
- 10.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- BrightFocus Foundation (A2013546S)
- National Institute of Neurological Disorders and Stroke (U54NS100693, R35NS097273, R01NS089544, R21NS094489)
- National Institute on Aging (ADRC 2 P50 AG016574–16)
- Mayo Clinic
- Liston Family Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, acetylation, phosphorylation, HDAC6, tau aggregation, microtubule stabilization, tauopathy, Alzheimer's disease
- MeSH terms
- Histone Deacetylase 6, Acetylation, Aged, Alzheimer Disease, Animals, Animals, Newborn, Cells, Cultured, Cerebral Cortex, Female, Histone Deacetylases, Humans, Lysine, Male, Mice, Transgenic, Mutation, Neurons, Phosphorylation, Protein Processing, Post-Translational, Serine, Tissue Banks, tau Proteins, Amino Acid Substitution, Tauopathies, Histone Deacetylase Inhibitors
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