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Editors Selection IGR 15-4

Basic research: Optineurin

Comment by Rand Allingham 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

See also comment(s) by Janey Wiggs •

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Mutations in optineurin (OPTN) have been associated with the development of POAG, most commonly a normal tension variant of this disease. OPTN is expressed in retinal ganglion cells and many other ocular and non-ocular tissues. One function of OPTN is to interfere with the action of tumor necrosis factor-a (TNF-α ). TNF-α participates in the apoptotic pathway through interaction with TNF receptor I. For this reason, it has been hypothesized that OPTN may play an important role in suppressing apoptosis. Therefore, in glaucomatous eyes, mutations of OPTN may increase apoptosis and retinal ganglion cell loss. In an elegant study, Kroeber et al. (358) examined the role of OPTN in suppressing apoptosis in a transgenic mouse model. A transgenic line of mice that expressed full length human OPTN utilizing a lens-specific promotor was created (&beta6; B1-crystallin OPTN). β B1-crystallin OPTN mice were crossbred with mice that overexpress TGF-β 1 (β B1-crystallin-TGF-β 1) using the same promotor. The β B1-crystallin-TGF-β 1 mouse line is used as a model for TGF-β 1-induced apoptotic cell death. In this manner lens cells in the crossed lines express both TGF-β 1 and OPTN and the effect of OPTN on TGF-β 1-induced apoptosis can be evaluated.

OPTN mutations may cause glaucoma by a mechanism other than lowering the threshold for apoptosis

The results conclusively demonstrated that expression of OPTN had no effect on TGF-β 1-induced apoptosis in this model. Furthermore, OPTN was not secreted into the aqueous humor in contrast with myocilin. The results of this study suggest that OPTN mutations may cause glaucoma by a mechanism other than lowering the threshold for apoptosis. However, as the investigators state, TGF-&beta6; 1 can induce apoptosis through pathways other than that medicated by TNF-α including the MAPK and mitochondrial pathways. Furthermore, apoptosis is cell-type and context specific, the role of OPTN in lens cells may differ significantly from its role in other tissues such as the optic nerve or trabecular meshwork. Therefore, although this study does not support the presence of an anti-apoptotic function for OPTN, additional studies are needed to further address this hypothesized mechanism of action.

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