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Cited by 11Alzheimer's disease research and treatmentsMicrotubule and mitosis dynamicsNeuroinflammation and Neurodegeneration Mechanisms

Tau phosphorylation impedes functionality of protective tau envelopes

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Siahaan, Valerie, Weissova, Romana, Karhanova, Adela, Lanska, Eva, Ruiz-Estrada, María J., Pukajová, Barbora, Dostál, Vojtěch, Henriot, Veronique +5 more·2026·Nature Chemical Biology
DOI 10.1038/s41589-025-02122-9PMC PMC13128492

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Abstract

Tau is an axonal microtubule-associated protein. Tau interaction with microtubules is regulated by phosphorylation. Hyperphosphorylation of tau is implicated in microtubule destabilization related to neurodegenerative disorders. However, how tau phosphorylation leads to microtubule destabilization is unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration can be explained by the disassembly and impaired functionality of the tau envelopes.

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  • Discontinuous patterning of tau along microtubules, consistent with envelopes, was observed in live non-neuronal U-2 OS cells following taxol treatment or elevated pH, and by immunofluorescence in fixed hippocampal neurons.

    “Discontinuous patterning of tau along microtubules, consistent with envelopes, was also observed in live, non-neuronal U-2 OS cells following taxol treatment (Siahaan et al., 2022) or with elevated pH (Siahaan et al., 2026), and by immunofluorescence staining in fixed hippocampal neurons (Tan et al., 2019).”

    From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Siahaan et al., 2026

    The Results section (‘Tau phosphorylation affects envelope formation in cells’; page unavailable) reports that elevated pH revealed separated tau patches along microtubules, consistent with tau envelopes. But the Methods section (‘Live-cell experiments’; page unavailable) identifies the cells used for elevated-pH live imaging as IMCD-3, not U-2 OS. The taxol and hippocampal-neuron observations are attached to other citations in the citing sentence. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Siahaan, V., Weissova, R., Karhanova, A., Lanska, E., Ruiz-Estrada, M. J., Pukajová, B., Dostál, V., Henriot, V., Janke, C., Libusová, L., Braun, M., Balastik, M., & Lansky, Z.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Czech Academy of Sciences (CZ)
  • Charles University (CZ)
Corresponding author
Braun, Marcus
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2026-01-27
Volume
22
Issue
5
Pages
759-769
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/s41589-025-02122-9
PMC
PMC13128492
OpenAlex
W7125814263
Cited by
11
References
3
Citations by year
2026: 10 · 2024: 1
FWCI
37.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Chemical Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
Funders
  • Univerzita Karlova v Praze (CZ.02.2.69/0.0/0.0/19\_073/0016935, 02.2.69/0.0/0.0/19_073/0016935)
  • Grantová Agentura, Univerzita Karlova (LX22NPO5107, CZ.02.2.69/0.0/0.0/19_073/0016935)
  • European Commission (LX22 NPO5107, CZ.02.1.01, LM2018140, CZ.02.1.01/0.0/0.0/18_046/0016045)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (LM2018129, LM2018129Czech-BioImaging, INFRA LM2018140, LM2023050, LM2023050 Czech‐BioImaging, CZ.02.1.01/0.0/0.0/18_046/0015974, LX22NPO5107, CZ.02.1.01/0.0/0.0/18_046/0016045, LM2018140, CZ.02.1.01, LM2023042, LM2018127)
  • Grantová Agentura České Republiky (CZ.02.1.01/0.0, LX22NPO5107, LM2018140, GA23-07703S, CZ.02.1.01, CZ.02.2.69/0.0/0.0/19 073/0016935, GX19-27477X, LM2018129, LM2018127)
  • Agentura Pro Zdravotnický Výzkum České Republiky
  • European Regional Development Fund (02.1.01/0.0/0.0, CZ.02.2.69/0.0/0.0/19_073/0016935, CZ.02.1.01/0.0/0.0/18_046/0015974, CZ.02, CZ.02.1.01, LM2018129, CZ.02.1.01/0.0/0.0/18_046/0016045, CZ.02.1.01/0.0/0.0, LM2018127, LX22NPO5107, LM2018140)
  • NextGenerationEU
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tau phosphorylation, tau hyperphosphorylation, microtubule destabilization, neurodegeneration, axonal microtubules
MeSH terms
Animals, Humans, Microtubules, Phosphorylation, tau Proteins

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