GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer's disease-like filaments
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.
Authors
- Pijush Chakraborty (ORCID: https://orcid.org/0000-0003-1749-5225)
- Jeffrey A. Purslow (ORCID: https://orcid.org/0000-0001-8828-0809)
- Sambhavi Puri
- Shannon Zhuang (ORCID: https://orcid.org/0000-0001-6416-5064)
- Markus Zweckstetter (ORCID: https://orcid.org/0000-0002-2536-6581)
- Simon A. Fromm (ORCID: https://orcid.org/0000-0002-2094-1911)
- Benjamin L. Wolozin (ORCID: https://orcid.org/0000-0003-2068-1475)
- Alain Ibáñez de Opakua (ORCID: https://orcid.org/0000-0003-1700-9354)
- Debdeep Chatterjee (ORCID: https://orcid.org/0000-0001-8153-8651)
- Milan Zachrdla (ORCID: https://orcid.org/0000-0002-5003-4669)
Institutions
- Boston University (US)
- German Center for Neurodegenerative Diseases (DE)
- European Molecular Biology Laboratory (DE)
- Laboratory Imaging (Czechia) (CZ)
- Center for Systems Biology (US)
- Tissue Dynamics (Israel) (IL)
- Max Planck Institute for Multidisciplinary Sciences (DE)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1073/pnas.2414176121
- Citations
- 43
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 10.05
Funders
- European Molecular Biology Laboratory
- European Commission
- Max-Planck-Gesellschaft
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Boehringer Ingelheim Stiftung
- HORIZON EUROPE European Research Council