Autophagy, a Critical Pathway in the Pathophysiology of Age-Related Macular Degeneration

Nady Golestaneh, PhD Georgetown University


Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. More than 11 million Americans are affected by AMD, and there is relatively little in the way of effective treatment until the disease become advanced. Autophagy is a self-eating process in the cells that involves degradation of unwanted cellular components to supply the cell with energy when needed. Failure in autophagy is related to diseases. We propose to study the role of autophagy and its possible dysfunction in AMD.

Project Details

This research is directed towards investigating the role of autophagy in the pathophysiology of age-related macular degeneration (AMD). Autophagy is a self-degradation process that breaks down cellular components to ensure cell survival during starvation. Autophagy also plays a housekeeping role in clearing damaged organelles, and is implicated in diseases that include cancer and metabolic and neurodegenerative disorders, in addition to normal aging. Dr. Golestaneh and colleagues have generated a physiologically relevant “disease in a dish model” that will allow to directly measure the efficiency of autophagy and its dysfunction in AMD. Determining dysfunction in autophagy and its underlying pathways will lead to better understanding the mechanisms of the disease and may lead to development of new drugs for treatment of AMD.

Details. The goal of this project is to examine the implication of autophagy in the pathophysiology of AMD. To do this, Dr. Golestaneh and colleagues are evaluating the efficiency of autophagy in degrading the proteins, lipids, and organelles, such as mitochondria, in retinal pigment epithelium (RPE) from AMD donors and comparing that with normal RPE. By comparing the efficiency of autophagy in diseased and normal RPE, the team aims to identify specific dysfunctional pathways, culprits in accumulation of waste products, called drusen, the hallmark of dry AMD. Because damage in mitochondria, the cellular energy producers, might also influence the efficiency of autophagy, the scientists are also examining mitochondrial function in AMD and the effect of mitochondrial activators and inhibitors on the efficiency of autophagy in diseased and normal RPE.

To date, little is known about the role of autophagy in the pathophysiology of AMD. This is mainly due to the lack of an adequate human in vitro AMD disease model that recapitulates many aspects of this multifactorial disease. The team has overcome this limitation by developing a physiologically relevant human AMD “disease in a dish” model that is a unique and reliable resource to study the role of autophagy in AMD.

This study supported by BrightFocus Foundation is directly investigating autophagy in a human AMD disease model, and will be able to establish whether the pathophysiological phenotypes identified by the research team in the diseased RPE are due to impaired autophagy. The successful completion of this project may lead to the discovery of new treatment strategies for AMD.