Project Details
Projekt
Regulation of Tau phase separation and strain formation by the Hsp90 chaperone system
Applicant
Professor Dr. Markus Zweckstetter
Subject Area
Structural Biology
Biophysics
Biophysics
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200
More than 30 neurodegenerative diseases including Alzheimer’s disease are associated with the pathological deposition of the intrinsically disordered protein Tau. Recent evidence suggests that Tau can undergo phase separation and form or partition into condensates in cells. These condensates may undergo liquid-to-solid phase transition thereby maturating into amyloid fibrils and contributing to the pathology of Alzheimer’s disease. In support of this hypothesis, we recently demonstrated that phosphorylation by GSK3ß, but not by several other kinases, promotes the aggregation of full-length Tau and enhances phase separation into gel-like condensates. Using cryoelectron microscopy we further showed that the fibrils that arise from condensates formed by GSK3ß-phosphorylated Tau adopt a fold comparable to that of paired helical filaments isolated from the brains of Alzheimer patients. Additionally, we demonstrated in another study that the molecular chaperone FKBP12 plays an important role in modulating Tau aggregation and neurotoxicity, and changes the structure of Tau fibrils formed when the chaperone is present while Tau aggregates. In yet other studies we revealed that HSP90 alone in complex with its co-chaperones binds unmodified monomeric Tau but not phosphorylated Tau, and modifies its aggregation by engaging in molecular complexes that were structurally characterized by us using a combination of NMR spectroscopy, mass spectrometry and molecular modelling. Based on these findings, our aim in the proposed project is to investigate the molecular mechanisms through which Hsp90 and its co-chaperones influence condensation of unmodified and post-translationally modified Tau, condensate aging of these Tau species towards aggregation and the formation of Tau fibril strains observed in different tauopathies. We propose to integrate condensation assays, NMR spectroscopy, mass spectrometry, high-resolution cryo-electron microscopy and molecular modelling to build a comprehensive model of how Hsp90 and its co-chaperones regulate Tau condensation and aggregation. The proposed project thus aims to provide important insights into Tau-driven pathological processes and identify potential targets for therapeutic intervention in neurodegenerative diseases.
DFG Programme
Research Units
