IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58737-y.html
   My bibliography  Save this article

A TLK2-mediated calcium-driven cell death pathway links neuronal degeneration to nuclear envelope disruption

Author

Listed:
  • Yajie Li

    (Capital Medical University
    Wenzhou Medical University)

  • Huaiyuan Huang

    (Capital Medical University)

  • Jingwen Gao

    (Capital Medical University)

  • Jinhong Lu

    (Capital Medical University)

  • Guifeng Kang

    (Capital Medical University)

  • Yipeng Ge

    (Chaoyang District)

  • Wencan Jiang

    (Laboratory of Beijing Tiantan Hospital and Capital Medical University
    Capital Medical University)

  • Xiang Cai

    (Wenzhou Medical University)

  • Guojun Zhang

    (Laboratory of Beijing Tiantan Hospital and Capital Medical University
    Capital Medical University)

  • Lei Liu

    (Capital Medical University
    Capital Medical University)

Abstract

Calcium overload drives neuronal cell death, but its mechanisms remain unclear. Previous studies in Drosophila implicated tousled-like kinase (TLK) in this process. Here, we investigated TLK2, the mammalian homolog, in calcium overload-induced neuronal death. We found that calcium overload enhances TLK2 expression, multimerization, and phosphorylation, increasing its kinase activity. Inhibiting TLK2 via RNA interference or a small-molecule inhibitor reduced neuronal death, while TLK2 overexpression triggered nuclear envelope (NE) rupture, nuclear enlargement, multinucleation, and cell cycle reentry markers. A protein complex involving TLK2, dynein light chain LC8, and myosin IIA was linked to NE disruption. In mouse models of glaucoma, TLK2 contributed to retinal ganglion cell degeneration, connecting calcium overload to neurodegeneration. We propose “CaToptosis” (Calcium-induced Tousled-like kinase-mediated cell death) as a distinct neuronal death pathway.

Suggested Citation

  • Yajie Li & Huaiyuan Huang & Jingwen Gao & Jinhong Lu & Guifeng Kang & Yipeng Ge & Wencan Jiang & Xiang Cai & Guojun Zhang & Lei Liu, 2025. "A TLK2-mediated calcium-driven cell death pathway links neuronal degeneration to nuclear envelope disruption," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58737-y
    DOI: 10.1038/s41467-025-58737-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58737-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58737-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58737-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.