2. Academic Validation
  3. A TLK2-mediated calcium-driven cell death pathway links neuronal degeneration to nuclear envelope disruption

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

  • Nat Commun. 2025 Apr 10;16(1):3419. doi: 10.1038/s41467-025-58737-y.
Yajie Li 1 2,  Huaiyuan Huang 1,  Jingwen Gao 1,  Jinhong Lu 1,  Guifeng Kang 3,  Yipeng Ge 4,  Wencan Jiang 5 6,  Xiang Cai 2,  Guojun Zhang 7 8,  Lei Liu 9 10
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology School of Basic Medicine, Capital Medical University, Youanmen, Beijing, 100069, China.
  • 2 Oujiang Laboratory, School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 3 School of Pharmaceutical Sciences, Capital Medical University, Youanmen, Beijing, 100069, China.
  • 4 Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road 2#, Chaoyang District, Beijing, 10029, China.
  • 5 Department of Clinical Diagnosis, Laboratory of Beijing Tiantan Hospital and Capital Medical University, Beijing, 100070, China.
  • 6 Laboratory diagnosis platform for nervous system infectious diseases, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100070, China.
  • 7 Department of Clinical Diagnosis, Laboratory of Beijing Tiantan Hospital and Capital Medical University, Beijing, 100070, China. guojun.zhang@ccmu.edu.cn.
  • 8 Laboratory diagnosis platform for nervous system infectious diseases, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100070, China. guojun.zhang@ccmu.edu.cn.
  • 9 Department of Biochemistry and Molecular Biology School of Basic Medicine, Capital Medical University, Youanmen, Beijing, 100069, China. leiliu@ccmu.edu.cn.
  • 10 Laboratory diagnosis platform for nervous system infectious diseases, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100070, China. leiliu@ccmu.edu.cn.
PMID: 40210858 DOI: 10.1038/s41467-025-58737-y
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.

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