Lipofuscin-Mediated Endoplasmic Reticulum Stress in the Pathogenesis of Macular Degeneration

As retinal pigment epithelium (RPE) gets old, it accumulates a lot of lipid bisretinoids (LBs). Above a certain threshold, or after exposure to light, LBs become toxic and may induce cell death. Many groups have previously identified mechanisms by which LBs damage the RPE. These studies, however, did not provide us with a method to clear LBs or alleviate their harmful effects. Working with cultures of RPE cells and synthetic LBs, we found a novel mechanism by which LBs kill RPE cells. This mechanism seems to be central to LB toxicity and is amenable to inhibition with drugs, as already we have identified two chemical compounds that fully prevent RPE cell death by LBs. Interestingly, some of these drugs are being tested for the treatment of neurodegeneration in Parkinson’s and Alzheimer’s disease. In the current project, we propose to fully characterize this new damaging mechanism, prove that it contributes significantly to LB-induced retinal degeneration in the eye, and test whether drugs that block this mechanism can prevent blindness in an animal model of AMD.

In the United States, age-related macular degeneration (AMD) is the foremost cause of irreversible vision loss in people over 70 years of age. Several factors contribute to the selective failure of this small area in the center of the retina that is responsible for humans’ most sharply focused vision. Among them: the macula contains by far the highest density of photoreceptors; it is irrigated only from underneath through choroid blood vessels; and it’s exposed to the highest levels of light. Light triggers visual impulses but also promotes the formation of all-trans-retinal (ATR), a form of vitamin A that is very toxic and needs to be recycled to prevent its self-conversion into dimeric forms, called lipid bisretinoids (LBs). LBs formed in the photoreceptors are dumped into the retinal pigment epithelium (RPE) which is in charge of keeping the retina clean. As RPE gets old, it accumulates a lot of LBs. Above a certain threshold, or after exposure to light, LBs become toxic and induce RPE cell death and subsequent photoreceptor cell death.

Many groups have previously investigated mechanisms by which LBs damage the RPE. The problem is, that these studies did not provide us with a method to clear LBs or alleviate their harmful effects. Working with cultures of RPE cells and synthetic LBs, we found a novel mechanism by which LBs kill RPE cells. The distinctive detail here is that this mechanism is amenable to drug therapy, as already we have identified two chemical compounds that fully prevent RPE cell death by LBs. Interestingly, some of these drugs have shown positive effects in the treatment of neurogenerative diseases, such as Parkinson’s and Alzheimer’s disease. In the current project, we propose to fully characterize this new damaging pathway, and test whether by targeting this pathway we can prevent blindness in animal models of LB-driven retinal disease.