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Cited by 96Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer’s disease-like filaments

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Chakraborty, Pijush, Ibáñez de Opakua, Alain, Purslow, Jeffrey A., Fromm, Simon A., Chatterjee, Debdeep, Zachrdla, Milan, Zhuang, Shannon, Puri, Sambhavi +2 more·2024·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2414176121PMC PMC11670061
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Abstract

The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown. Here, we show that the serine/threonine kinase GSK3β catalyzes the aggregation of the protein tau into Alzheimer’s disease (AD)-like filaments. We demonstrate that phosphorylation by GSK3β, but not by several other kinases, promotes the aggregation of full-length tau as well as enhances phase separation into gel-like condensate structures. Cryoelectron microscopy further reveals that the fibrils formed by GSK3β-phosphorylated tau adopt a fold comparable to that of paired helical filaments isolated from the brains of AD patients. Our results elucidate the intricate relationship between posttranslational modification and the formation of tau strains in neurodegenerative diseases.

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Authors
Chakraborty, P., Ibáñez de Opakua, A., Purslow, J. A., Fromm, S. A., Chatterjee, D., Zachrdla, M., Zhuang, S., Puri, S., Wolozin, B., & Zweckstetter, M.
Affiliations
  • Max Planck Society (DE)
  • German Center for Neurodegenerative Diseases
  • German Center for Neurodegenerative Diseases (DE)
  • European Molecular Biology Laboratory (ES)
  • Boston University (US)
Corresponding author
Zweckstetter, Markus
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2024-12-18
Volume
121
Issue
52
Pages
e2414176121-e2414176121
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2414176121
PMC
PMC11670061
OpenAlex
W4405523752
Cited by
96
References
5
Citations by year
2026: 69 · 2025: 24 · 2024: 3
FWCI
24.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DZNE Pub (submittedVersion, cc-by)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders
EC | ERC | HORIZON EUROPE European Research Council (787679)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
GSK3β, tau phosphorylation, tau aggregation, Alzheimer's disease, paired helical filaments, phase separation, protein condensates, post-translational modification, neurodegeneration, protein aggregation
MeSH terms
Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Brain, Humans, Phosphorylation, Protein Processing, Post-Translational, tau Proteins, Cryoelectron Microscopy, Protein Aggregation, Pathological, Protein Aggregates

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