GSK3β phosphorylation catalyzes the aggregation of Tau into Alzheimer's disease-like amyloid strain

Chakraborty, P.; Ibanez de Opakua, A.; Purslow, J. A.; Fromm, S. A.; Chatterjee, D.; Zachrdla, M.; Puri, S.; Wolozin, B.; Zweckstetter, M.

doi:10.1101/2023.12.19.572292

bioRxiv · 10.1101/2023.12.19.572292

GSK3β phosphorylation catalyzes the aggregation of Tau into Alzheimer's disease-like amyloid strain

Chakraborty, P.·Ibanez de Opakua, A.·Purslow, J. A.·Fromm, S. A.·Chatterjee, D.·Zachrdla, M.·Puri, S.·Wolozin, B.·Zweckstetter, M.

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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 GSK3{beta} catalyzes the aggregation of the protein tau into an Alzheimers disease-like amyloid strain. We demonstrate that phosphorylation by GSK3{beta}, but not by several other kinases, promotes the aggregation of full-length tau through enhanced phase separation into gel-like condensate structures. Cryo-electron microscopy further reveals that the amyloid fibrils formed by GSK3{beta}-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 post-translational modification and the formation of tau strains in neurodegenerative diseases.

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Chakraborty, P., Ibanez de Opakua, A., Purslow, J. A., Fromm, S. A., Chatterjee, D., Zachrdla, M., Puri, S., Wolozin, B., Zweckstetter, M.. 2023-12-19. GSK3β phosphorylation catalyzes the aggregation of Tau into Alzheimer's disease-like amyloid strain. https://doi.org/10.1101/2023.12.19.572292

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