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Peer-reviewedCC BY 4.0Communications Biology

A pathological phosphorylation pattern enhances tau cooperativity on microtubules and facilitates tau filament assembly

  • Xiangyu Fan1,2,3,4
  • Joey B. Truong1,4
  • Kyoko Okada1,4
  • Henry Lin1,4
  • Kassandra M. Ori-McKenney1,4
  • Richard J. McKenney5
5 affiliations
  1. 1Department of Molecular and Cellular Biology, University of California, Davis, CA, USA
  2. 2Henan Provincial Engineering Centre for Tumor Molecular Medicine, Henan University, Kaifeng, China
  3. 3School of Basic Medical Sciences, Henan University, Kaifeng, China
  4. 4University of California - Davis
  5. 5Department of Molecular and Cellular Biology, University of California, Davis, CA, USA. [email protected]
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Abstract

Phosphorylation of the microtubule-associated protein tau plays important roles in both normal physiology and disease. While tau phosphorylation levels are similarly elevated in processes such as fetal development and hibernation and in pathological states like Alzheimer’s disease, the pattern of phosphorylation differs between these contexts. Whether distinct phosphorylation patterns differentially impact tau’s function on microtubules and its propensity to form neurofibrillary tangles (NFTs) has remained unclear. Here we investigated how differential phosphorylation affects microtubule binding, cooperative tau envelope formation, and NFT-relevant filament assembly. Consistent with prior work, phosphorylation decreases tau’s overall microtubule affinity. However, we find that phosphorylation more dramatically impacts cooperativity between tau molecules during envelope formation. Strikingly, the specific pattern of phosphorylation, rather than overall level, strongly promotes tau filament assembly in vitro. These findings provide insights into how tau phosphorylation modulates its physiological microtubule interactions and its pathoconversion into NFTs.

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Cite

BibTeXRIS
BibTeX
@article{fan2026pathological,
  title = {{A pathological phosphorylation pattern enhances tau cooperativity on microtubules and facilitates tau filament assembly}},
  author = {Xiangyu Fan and Joey B. Truong and Kyoko Okada and Henry Lin and Kassandra M. Ori-McKenney and Richard J. McKenney},
  journal = {Communications Biology},
  year = {2026},
  month = aug,
  doi = {10.1038/s42003-026-10797-6},
  url = {https://doi.org/10.1038/s42003-026-10797-6},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A pathological phosphorylation pattern enhances tau cooperativity on microtubules and facilitates tau filament assembly
AU  - Xiangyu Fan
AU  - Joey B. Truong
AU  - Kyoko Okada
AU  - Henry Lin
AU  - Kassandra M. Ori-McKenney
AU  - Richard J. McKenney
PY  - 2026
DA  - 2026/08/21
JO  - Communications Biology
DO  - 10.1038/s42003-026-10797-6
UR  - https://doi.org/10.1038/s42003-026-10797-6
AB  - Phosphorylation of the microtubule-associated protein tau plays important roles in both normal physiology and disease. While tau phosphorylation levels are similarly elevated in processes such as fetal development and hibernation and in pathological states like Alzheimer’s disease, the pattern of phosphorylation differs between these contexts. Whether distinct phosphorylation patterns differentially impact tau’s function on microtubules and its propensity to form neurofibrillary tangles (NFTs) has remained unclear. Here we investigated how differential phosphorylation affects microtubule binding, cooperative tau envelope formation, and NFT-relevant filament assembly. Consistent with prior work, phosphorylation decreases tau’s overall microtubule affinity. However, we find that phosphorylation more dramatically impacts cooperativity between tau molecules during envelope formation. Strikingly, the specific pattern of phosphorylation, rather than overall level, strongly promotes tau filament assembly in vitro. These findings provide insights into how tau phosphorylation modulates its physiological microtubule interactions and its pathoconversion into NFTs.
SN  - 2399-3642
ER  -