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D. Balasubramanian, M. Chalasani, V. Radha, V. Gupta, N. Agarwal, G. Swarup; A Glaucoma-Associated Mutant of Optineurin Selectively Induces Death of Retinal Ganglion Cells Which Is Inhibited by Antioxidants. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5550.
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Certain missense mutations in the coding region of the optineurin gene (OPTN) are associated with normal tension glaucoma as well as POAG. While the function of the optineurin protein is yet to be elucidated, its most common mutation, E50K, is associated with a severe phenotype. In the present study we have explored some of the functional characteristics of optineurin and its mutants, in particular E50K.
Plasmids expressing normal or wild type (WT)optineurin, and E50K, R545Q, H26D and H486R mutants of optineurin were prepared. They were then transfected into HeLa, Cos-1, IMR32 and the rat retinal ganglion cell line RGC-5 and their effects on cell survival was monitored by morphological observation of cells. Their effects on tumor necrosis factor-α-induced cell death were also analyzed. Expression of optineurin and its mutants was monitored by immunofluorescence staining of cells and also by Western blotting.
The E50K mutant was seen to selectively induce the death of rat retinal ganglion cells (RGC-5) but not of the other cell lines tested (Cos-1, HeLa & IMR-32). Neither the other mutants nor WT optineurin were seen to do so. This cell death was seen to require capases-1 & 9, and was inhibited by Bcl-2 and. It was also inhibited by antioxidants N-acetyl cysteine and Trolox, and by the free radical scavenger superoxide dismutase (MnSOD). While expression of wild type and E50K mutant suppressed cell death induced by TNF-α in HeLa cells, they were seen to potentiate such cell death in RGC-5 cells.
The E50K mutant of optineurin has acquired the ability to induce cell death selectively in retinal ganglion cells. This cell death is mediated by oxidative stress, since it is inhibited by antioxidants and by MnSOD. Our findings thus raise the possibility of the use of antioxidants for delaying or controlling some forms of glaucoma.
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