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<p>Calcium overload drives neuronal cell death, but its mechanisms remain unclear. Previous studies in <i>Drosophila</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月10日

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  • Yajie Li,
  • Huaiyuan Huang,
  • Jingwen Gao,
  • Jinhong Lu,
  • Guifeng Kang,
  • Yipeng Ge,
  • Wencan Jiang,
  • Xiang Cai,
  • Guojun Zhang,
  • Lei Liu

摘要

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.