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Editors Selection IGR 14-2

Basic research: Optineurin

Comment by Janey Wiggs on:

13756 Transgenic studies on the role of optineurin in the mouse eye, Kroeber M; Ohlmann A; Russell P et al., Experimental Eye Research, 2006; 82: 1075-1085

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At least ten genetic loci have been found for open angle glaucoma (GLC1A-K) using large pedigrees and mendelian linkage approaches and an additional four regions (14q, 15q, 2q and 10p) have been defined as containing glaucoma susceptibility genes from sibpair-based whole genome analyses. The optineurin gene was identified as the causative gene for GLC1E by Rezaie and collaborators in 2002. Subsequent studies have shown that mutations in optineurin, particularly the E50K mutation, are a rare cause of normal tension glaucoma. Because of the association between mutations in optineurin and normal tension glaucoma, it has been hypothesized that loss of optineurin function increases apoptosis of retinal ganglion cells. To study the effect of optineurin on apoptosis, Kroeber et al. (358) created a transgenic mouse that overexpressed ectopic optineurin in their lenses and crossed these mice with another transgenic mouse with apoptosis of developing lens fibers caused by overexpressed ectopic TGF-β 1. The results of this experiment showed similar phenotypes in both the transgenic TGF-β 1 mice and the double transgenic animals containing ectopic optineurin in addition to the TGF-β 1. Measures of apoptosis including TUNEL staining of lens fiber nuclei and electron microscopy of lens fibers showed equal amounts of apoptosis in the double transgenic mice compared with the TGF-β 1 only mice, indicating that in the lens optineurin did not prevent TGF-β 1 mediated apoptosis. Previous studies have suggested that optineurin may protect against TNF-α induced apoptosis of retinal ganglion cells. TGF-β 1 can interact with TNF-α to induce apoptosis through mitogen activated protein kinase signaling or the mitochondrial apoptotic pathway. The results of this study showing that optineurin does not inhibit TGF-β 1 induced apoptosis argue that optineurin does not modulate a similar apoptotic mechanism in retinal ganglion cells. However, it remains a possibility that optineurin function is cell specific and that the protein is capable of preventing apoptosis caused by TGF-&beta6; 1 and TNF-α in retinal ganglion cells and not lens cells. Further experiments investigating the role of optineurin in retinal ganglion cell apoptosis are needed to address this important question.

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