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Glaucoma is a leading cause of irreversible blindness worldwide that is characterized by progressive retinal ganglion cell (RGC) death. However, RGC senescence as a phase before RGC death, and the mechanism of RGC senescence remains unclear. Here, we demonstrate that TANK-binding protein 1 (TBK1) is upregulated in acute IOP elevation-induced ischemic retinas mouse model. Moreover, pre-treatment with the TBK1 inhibitor BX-795 reduced p16INK4a (p16) expression and RGC senescence. Upregulation of TBK1 via plasmid transfection increased Akt phosphorylation at Ser473 and Bmi1 phosphorylation. The Akt inhibitor MK-2206 decreased the expression of p16 and Bmi1 serine phosphorylation. A Bmi1 Ser316 mutation also attenuated TBK1-induced p16 upregulation. Finally, silencing of TBK1 via shRNA knockdown reduced the expression of p16 as well as Akt and Bmi1 phosphorylation, reducing RGC senescence  in vivo . These data suggest that acute IOP elevation-induced ischemia increases TBK1 expression, which then increases p16 expression through the Akt- Bmi1 phosphorylation pathway. This study therefore elucidates a novel mechanism whereby TBK1 regulates p16 expression and RGC senescence, suggesting a potential novel treatment strategy for minimizing RGC senescence in retinal ischemia and glaucoma.

P16INK4a upregulation mediated by TBK1 induces retinal ganglion cell senescence in ischemic injury