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

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

SUBMITTER: Li Y 

PROVIDER: S-EPMC11986041 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature