Journal Article

DZNE-2025-00044

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer's disease-like filaments.

Chakraborty, P.Extern* ; Ibáñez de Opakua, A.DZNE* ; Purslow, J.DZNE* ; Fromm, S. A. ; Chatterjee, D.DZNE* ; Zachrdla, M.DZNE* ; Zhuang, S.DZNE* ; Puri, S. ; Wolozin, B. ; Zweckstetter, M. (Last author)DZNE*

2024
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.2414176121

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.

Keyword(s): tau Proteins: metabolism (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Phosphorylation (MeSH) ; Humans (MeSH) ; Glycogen Synthase Kinase 3 beta: metabolism (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Cryoelectron Microscopy (MeSH) ; Protein Aggregates (MeSH) ; Alzheimer's disease ; NMR ; cryo-EM ; phosphorylation ; tau ; tau Proteins ; Glycogen Synthase Kinase 3 beta ; MAPT protein, human ; Protein Aggregates ; GSK3B protein, human

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Contributing Institute(s):

1. Translational Structural Biology (AG Zweckstetter)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Chakraborty, P.DZNE* ; Ibanez de Opakua, A.DZNE* ; Purslow, J.DZNE* ; Fromm, S. ; Chatterjee, D.DZNE* ; Zachrdla, M.DZNE* ; Zhuang, S.DZNE* ; Puri, S. ; Wolozin, B. ; Zweckstetter, M.DZNE*
Dataset: Cryo electron micrographs of GSK3β phosphorylated tau fibrils
EMPIAR (2025) [10.6019/EMPIAR-12698]2025 BibTeX | EndNote: XML, Text | RIS

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