Cited by 145Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

An acetylation–phosphorylation switch that regulates tau aggregation propensity and function

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Carlomagno, Yari, Chung, Dah-eun Chloe, Yue, Mei, Castanedes-Casey, Monica, Madden, Benjamin J., Dunmore, Judy, Tong, Jimei, DeTure, Michael +3 more·2017·Journal of Biological Chemistry

Abstract

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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Crossref · 10.1074/jbc.m117.794602

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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
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2017-09
Volume
292
Issue
37
Pages
15277-15286
ISSN
0021-9258 (ISSN-L)
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
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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