Photoreceptor death is the ultimate cause of vision loss in many retinal disorders. Photoreceptors die when they are physically separated from the underlying retinal pigment epithelium (RPE) and choroidal vessels, which provide metabolic support to the outer layers of the retina. Retinal detachment occurs in various retinal disorders, including age-related macular degeneration (AMD) [1
], diabetic retinopathy [2
], as well as rhegmatogenous retinal detachment. Although surgery is carried out to reattach the retina, only two-fifths of patients with rhegmatogenous retinal detachment involving the macula recover 20/40 or better vision. Histological examination of the retina in experimental retinal detachment, which is created by subretinal injection of sodium hyaluronate in animal eyes, showed that photoreceptor death is first identified at 12 hours, peaked by around 3 days, and dropped to a low level by 7 days after retinal detachment (Fig. ) [3
]. Interestingly, the retina in patients with rhegmatogenous retinal detachment exhibits a similar pattern and time course of photoreceptor death observed in experimental retinal detachment [6
]. These studies suggest that photoreceptor death may be one of the causes of vision loss after retinal detachment.
AMD is the most common cause of adult blindness in the western world [7
]. Severe vision loss in late stage AMD results from choroidal neovascularization (called wet or neovascular AMD) or geographic atrophy (called dry AMD) [8
]. In wet AMD, choroidal neovascular vessels leak serous or hemorrhagic fluid, causing detachment of RPE or photoreceptors, subretinal or intraretinal hemorrhage, and consequent fibrovascular scarring. Although anti-vascular endothelial growth factor (VEGF) therapies have shown visual improvement in many patients with neovascular AMD [9
], some patients still do not respond to these therapies and 2/3 of patients do not have visual improvement. Because photoreceptor loss underlies the pathology of AMD [12
], neuroprotective agents targeting photoreceptor death may be used in combination with anti-VEGF therapies to improve visual outcomes. In dry AMD, geographic atrophy is a serious cause of vision loss. It results from a slowly progressive atrophy of RPE and photoreceptors. Histological studies of geographic atrophy have suggested that RPE cells die first, followed by degeneration of photoreceptors [1
]. On the other hand, macular translocation studies have shown that RPE atrophy recurs under the translocated macula after surgery, suggesting the possibility that photoreceptors may cause RPE degeneration in geographic atrophy or that RPE cells are impaired in handling the metabolic/trophic demands of the macular photoreceptors. [14
In other retinal degenerative disorders such as retinitis pigmentosa, photoreceptor death is the basis for visual decline [17
]. Retinitis pigmentosa is a group of inherited retinal disorders, affecting over 1 million individuals worldwide. Although genetic analyses have identified over 40 different genetic mutations [Retinal Information Network (RetNet) at http://www.sph.uth.tmc.edu/Retnet/
], the mechanisms by which these mutations cause photoreceptor death are unclear and these diseases remain intractable [18
]. Therefore, identification of the mechanisms involved in photoreceptor death is critical to developing new treatment strategies for these retinal disorders associated with photoreceptor loss.