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Anitha Krishnan, Alexander Jones, Ann Marshak Rothstein, Bruce R Ksander, Meredith S Gregory-Ksander; Soluble Fas ligand is a neuroprotective molecule critical in restricting glaucomatous damage to retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2194.
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Glaucoma is an ocular disease characterized by the specific loss of retinal ganglion cells (RGC) and their axons. However, several electroretinography studies in human and animal models of glaucoma indicate a functional loss in both the inner and outer retinal layers, suggesting that all layers of the retina are affected during glaucoma. We demonstrated previously that Fas ligand (FasL) is a pro-apoptotic molecule that mediates apoptosis of RGCs in glaucoma. However, the pro-apoptotic membrane form of FasL (mFasL) can also be cleaved to release a soluble molecule (sFasL) that is not apoptotic. We hypothesize that sFasL is neuroprotective and the cleavage of mFasL and release of sFasL during glaucoma is critical in protecting other retinal neurons and limiting the cell death to the RGC layer.
FasL knock-in mouse (ΔCS.1) that only express mFasL and no sFasL were backcrossed with DBA/2J mice (D2.ΔCS mice) that develop spontaneous elevated intraocular pressure (IOP) and loss of RGCs. D2.ΔCS mice were compared with D2 littermates. Groups of mice were aged up to 12 months and examined for age-related: (i) IOP (Tonolab), (ii) iris atrophy and pigment dispersion, (iii) loss of RGCs and optic nerve axons (beta tubulin and PPD staining), and (iv) retinal degeneration (H&E, TUNEL, GFAP, and glutamine synthetase).
D2 and D2.ΔCS mice displayed a similar age-related (i) increase in IOP, and (ii) pigment dispersion and iris atrophy. However, in the absence of sFasL the D2.ΔCS mice not only displayed accelerated loss of RGCs but also extensive degeneration of both the inner and outer nuclear layers (INL, ONL) of the retina. Apoptosis was observed in both the INL and ONL of D2.ΔCS mice as early as 6 months, while apoptosis was restricted to the RGC layer in D2 littermates. H&E revealed a significant loss of cells in all retinal layers of the D2.ΔCS mice by 12 months of age and this retinal degeneration coincided with a loss of muller cells.
Soluble FasL is an important neuroprotective molecule that slows the loss of RGCs and prevents destruction of other retinal neurons during glaucoma. Therefore, we predict that enhanced cleavage of mFasL to produce more sFasL will completely protect RGCs even during glaucomatous-inducing stress.
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