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    Home > Biochemistry News > Biotechnology News > The latest paper by the Academy of Biological Sciences of Wuhan University reveals the molecular mechanism of zinc ions regulating Tau protein phase separation and cytotoxicity

    The latest paper by the Academy of Biological Sciences of Wuhan University reveals the molecular mechanism of zinc ions regulating Tau protein phase separation and cytotoxicity

    • Last Update: 2022-05-17
    • Source: Internet
    • Author: User
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      On April 19, the International Journal of Biological Macromolecules (impact factor 6.
    953) published the latest research results of Prof.
    Yi Liang online in the form of a Research Article, titled "Zinc enhances liquid-liquid phase separation of Tau protein and aggravates mitochondrial "damages in cells" (zinc ions promote the liquid-liquid phase separation of Tau protein and aggravate mitochondrial damage caused by Tau aggregation), this work found that zinc ions can promote the co-localization and interaction of Tau protein and G3BP1 in cells, thereby promoting the liquid-liquid phase of Tau protein.
    - Liquid phase separation, aggravates the mitochondrial damage caused by Tau aggregation and promotes Tau protein toxicity, revealing the molecular mechanism of zinc ion regulating Tau protein phase separation and cytotoxicity

    .

      Alzheimer's disease (AD) is a neurodegenerative disease with the highest incidence in today's society, and the number of patients is increasing.
    Tau protein undergoes pathological phosphorylation modification and misfolding in neurons to form regular fibrotic aggregates (neurons).
    Fibrillary tangles) is an important pathological feature of AD

    .
    Both Tau protein and zinc ions in the human body are mainly enriched in the axons of nerve cells in the human central nervous system

    .
    Zinc ion is an important trace element and inorganic ion in the human body, and its homeostasis regulation plays an important role in the normal operation of life activities; the imbalance of zinc ion homeostasis plays a key role in the occurrence and development of various diseases, including neurodegenerative diseases , in the brains of AD patients, the content of zinc ions was significantly increased

    .
    Liquid-liquid phase separation of Tau can lead to its misfolding and aggregation in neural cells

    .
    However, it is unclear whether zinc ions can regulate the formation of Tau droplets in cells and whether they can exacerbate Tau aggregation-induced mitochondrial damage

    .

      Preliminary work on protein disulfide isomerase (PDI) and myricetin regulating Tau protein phase separation, autophagy and toxicity (published in Journal of Molecular Biology and Journal of Molecular Biology on March 27, 2020 and September 22, 2021, respectively of Biological Chemistry ), Professor Liang Yi's research team revealed the regulatory mechanism of PDI on the formation, aggregation and toxicity of Tau protein droplets and its role in AD, and explained that PDI and its thiol nitrosylation regulate Tau phase separation And the molecular mechanism of the disease is found.
    It is found that the natural flavonoid myricetin can slow down the liquid-liquid phase separation of Tau protein, activate autophagy to inhibit the toxicity of Tau protein, and reveal the molecular mechanism of Tau protein phase separation and autophagy regulation

    .

      In this study, Prof.
    Liang Yi's research team used laser confocal microscopy, turbidity measurement and fluorescence bleaching recovery methods to report that pathological concentrations of zinc ions not only significantly promoted the liquid-liquid phase separation of full-length Tau protein, but also The boundary migrated to lower protein concentrations and also significantly promoted pathological phosphorylation and misfolding of Tau in neural cells

    .
    At the same time, the research team used laser confocal microscopy, co-immunoprecipitation and western blotting to find that zinc ions promote the co-localization and interaction of Tau protein and G3BP1 in cells by binding to Cys291 and Cys322 of full-length Tau protein, thereby promoting Tau Liquid-liquid phase separation of proteins and formation of stress granules, while zinc ions exacerbate Tau aggregation-induced mitochondrial damage and reactive oxygen species (ROS) upregulation and trigger cytotoxicity

    .
    The experimental results of this work suggest that zinc ions are negative regulators of Alzheimer's disease (AD)

    .

      The findings of this work reveal for the first time the regulatory mechanism of zinc ions on Tau droplet formation, mitochondrial damage, and Tau protein toxicity in cells, elucidating the role of zinc homeostasis and Tau protein phase separation in AD pathogenesis, so zinc As a negative regulator of neurodegenerative diseases such as AD, ions play an important role in promoting the liquid-liquid phase separation of Tau and aggravating the mitochondrial damage caused by Tau aggregation, providing a new perspective for the targeted therapy of AD with inorganic ions, and also for the treatment of AD.
    The cause and occurrence of AD and early diagnosis provide useful clues and have important scientific significance

    .

      Wuhan University is the first signatory unit, Gao Yingying, a 2018 doctoral student of the School of Life Sciences, is the first author, Zhong Tao, a 2021 doctoral student, is the co-first author, and Professor Liang Yi is the corresponding author
    .
    This research work was supported by the National Natural Science Foundation of China and the Ministry of Science and Technology

    .

    ▲ Zinc ions promote the co-localization of Tau protein and G3BP1 in cells
    .
    It is confirmed that zinc ion promotes the co-localization of full-length Tau protein and G3BP1 in cells, thereby promoting the occurrence of phase separation of Tau protein in cells


    ▲ Zinc ions promote the interaction between Tau protein and G3BP1


    ▲ Zinc ions exacerbate Tau aggregation-induced mitochondrial damage and up-regulation of reactive oxygen species (ROS)


    Paper link: https://doi.
    org/10.
    1016/j.
    ijbiomac.
    2022.
    04.
    034


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