TY  - JOUR
AU  - Chakraborty, Pijush
AU  - Ibáñez de Opakua, Alain
AU  - Purslow, Jeffrey
AU  - Fromm, Simon A
AU  - Chatterjee, Debdeep
AU  - Zachrdla, Milan
AU  - Zhuang, Shannon
AU  - Puri, Sambhavi
AU  - Wolozin, Benjamin
AU  - Zweckstetter, Markus
TI  - GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer's disease-like filaments.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 121
IS  - 52
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DZNE-2025-00044
SP  - e2414176121
PY  - 2024
AB  - 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.
KW  - tau Proteins: metabolism
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Phosphorylation
KW  - Humans
KW  - Glycogen Synthase Kinase 3 beta: metabolism
KW  - Protein Aggregation, Pathological: metabolism
KW  - Protein Processing, Post-Translational
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Cryoelectron Microscopy
KW  - Protein Aggregates
KW  - Alzheimer's disease (Other)
KW  - NMR (Other)
KW  - cryo-EM (Other)
KW  - phosphorylation (Other)
KW  - tau (Other)
KW  - tau Proteins (NLM Chemicals)
KW  - Glycogen Synthase Kinase 3 beta (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - GSK3B protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39693350
C2  - pmc:PMC11670061
DO  - DOI:10.1073/pnas.2414176121
UR  - https://pub.dzne.de/record/274063
ER  -