2. Academic Validation
  3. Fyn-dependent Tau microcluster formation seeds and boosts extensive Tau pathology

Fyn-dependent Tau microcluster formation seeds and boosts extensive Tau pathology

  • Acta Neuropathol. 2025 May 14;149(1):48. doi: 10.1007/s00401-025-02887-2.
Yingjie Li 1,  Wending Qi 2,  Le Chen 1,  Fan Chu 1,  Wenfeng Jiang 3,  Zifeng Xu 3,  Yuexin Luo 4,  Xubo Hu 3,  Jürgen Götz 5,  Chuanzhou Li 6
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 First Clinic School, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, St Lucia Campus, Brisbane, QLD, Australia. j.goetz@uq.edu.au.
  • 6 Department of Medical Genetics, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. chuanzhouli@hust.edu.cn.
PMID: 40366450 DOI: 10.1007/s00401-025-02887-2
Abstract

Tau seeding and propagation are defining features of all tauopathies, including Alzheimer's disease, but the underlying molecular drivers remain incompletely understood. Here, we reveal that Fyn expression boosts massive Tau pathology in the mouse brain and enhances Tau seeding induced by pathological Tau seeds in biosensor cells. However, even in the absence of seeds, Fyn itself, via its palmitoylation, triggers the de novo formation of small, plasma membrane-anchored Tau microclusters, which initiate pronounced and diverse intra- and transcellular Tau seeding in vitro and in vivo. Mechanistically, membrane-associated Fyn phosphorylates Tau at its Tyr310 epitope and then recruits and activates GSK3β locally, which further phosphorylates Tau at Ser/Thr sites in the microclusters, eliciting their full seeding capacity. Our data suggest that Fyn not only serves as a master switch that initiates Tau pathogenesis on its own, but also augments a pre-existing Tau pathology, leading to a vicious cycle of Tau aggregation.

Keywords

Aggregation; Alzheimer’s disease; Fyn; Seeding; Tau; Tauopathy.

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