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Editors Selection IGR 9-4

Retinal ganglion cells: Glial stress in glaucoma model

Comment by Robert Nickells on:

19484 Regulation of cell death and survival pathways in experimental glaucoma, Levkovitch-Verbin H; Harizman N; Dardik R et al., Experimental Eye Research, 2007; 85: 250-258

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Retinal ganglion cell soma death in glaucoma is mediated by a complex series of molecular events that we are only really beginning to fully understand. Several important studies have been conducted in the last decade to help elucidate the process, beginning with the finding that these cells execute an intrinsic apoptotic program in response to the damage elicited by ocular hypertension. Levkovitch-Verbin et al. (903) build on this by examining the expression patterns of several key signal transduction molecules involved in both cell death activation and cell stress response pathways. The study uses one of several rat models of experimental ocular hypertension and changes in expression/or protein activation, were conducted using immunohistochemistry on frozen sections of retina harvested from eyes during the first 30 days of induced elevated IOP. Using a semi-quantitative approach of counting positive cells over a normalized distance of the ganglion cell layer, this group found that cells in this layer activate both survival and apoptotic signaling pathways. This concept, in itself is not new, as several investigators have documented the activation of both cell survival proteins and pro-apoptotic signaling proteins in experimental glaucoma. This study, however, shows the temporal activation of individual signaling pathways in the same eyes and gives us a clue to the major pathways turned on in ganglion cells.

The temporal activation of individual signaling pathways in the same eyes gives us a clue to the major pathways turned on in ganglion cells

Overall, it marks an important step in our understanding of the molecular contortions ganglion cells put themselves through in an effort to survive IOP-related stresses, while at the same time engineering their own suicide. Although interesting, this study also leaves some important questions unaddressed. The authors equate glaucoma to ocular hypertension without any validation that any of their animals experienced significant ganglion cell loss. This is an important consideration when drawing conclusions about the signaling molecules involved in cell death. As a surrogate, however, they document relatively late activation of active caspase 3, one of the critical proteases in the caspase cascade that is responsible for the final self-destruction of the cell soma. Since we already understand much of the role that the pro-apoptotic protein BAX plays in the death of ganglion cells, we are now converging on the critical players between early signal transduction and BAX function leading to caspase activation. Given what is known about the signaling molecules documented in this study, it is likely that greater attention will now be turned to the BH3-domain only proteins.

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