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Ferroptosis promotes microtubule-associated protein tau aggregation via GSK-3β activation and proteasome inhibition

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Abstract

Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. Iron dyshomeostasis and peroxidation damage of neurons in some particular brain regions are closely related to a wide range of neurodegenerative diseases known as “tauopathies,” in which intracellular aggregation of microtubule-associated protein tau is the common neuropathological feature. However, the relationship between ferroptosis and tau aggregation is not well understood. The current study demonstrates that erastin-induced ferroptosis can promote tau hyperphosphorylation and aggregation in mouse neuroblastoma cells (N2a cells). Moreover, ferroptosis inhibitor ferrostatin-1 can alleviate tau aggregation effectively. In-depth mechanism research indicates that activated glycogen synthase kinase-3β (GSK-3β) is responsible for the abnormal hyperphosphorylation of tau. More importantly, proteasome inhibition can exacerbate tau degradation obstacle and accelerate tau aggregation in the process of ferroptosis. Our results indicate that ferroptosis can lead to abnormal aggregation of tau protein and might be a promising therapeutic target of tauopathies.

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The data are available upon reasonable request from the author for correspondence.

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Acknowledgements

We thank all the members of our research team for their help and support from School of Life Sciences, Central China Normal University.

Funding

This work was supported by the project of Hubei Key Laboratory of Genetic Regulation and Integrative Biology (No. GRIB201905) and National Natural Science Foundation of China (No. 81771150, 22076061, and 41601543). Hubei Provincial Key Laboratory of Intelligent Robot,No. GRIB201905,Xiaomei Liao,National Natural Science Foundation of China,81771150,Shaohui Wang,22076061,Hongwei Sun,41601543,Hongwei Sun

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Author notes

  1. Shaohui Wang, Yao Jiang and Yabo Liu contributed equally to this study

Authors and Affiliations

  1. Hubei Key Lab of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, People’s Republic of China

    Shaohui Wang, Yao Jiang, Yabo Liu, Qianhui Liu, Mengjie Mei & Xiaomei Liao

  2. Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Institute of Environmental & Applied Chemistry, College of Chemistry, Central China Normal University, Wuhan, 430079, People’s Republic of China

    Hongwei Sun & Xiaomei Liao

Authors
  1. Shaohui Wang
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  2. Yao Jiang
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  3. Yabo Liu
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  4. Qianhui Liu
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  5. Hongwei Sun
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  6. Mengjie Mei
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  7. Xiaomei Liao
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Contributions

XM-L conceived the experiments and supervised the project. YJ and YB-L performed the experiments. SH-W collected the data, made the figures, and wrote the manuscript. MJ-M did the analysis. HW-S contributed essential reagents or tools. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiaomei Liao.

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This experiment was approved by the Ethics Committee of Central China Normal University.

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Wang, S., Jiang, Y., Liu, Y. et al. Ferroptosis promotes microtubule-associated protein tau aggregation via GSK-3β activation and proteasome inhibition. Mol Neurobiol 59, 1486–1501 (2022). https://doi.org/10.1007/s12035-022-02731-8

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  • DOI: https://doi.org/10.1007/s12035-022-02731-8

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