Targeting Drusen Production in the AMD Retina
What: Scientists discovered how a combination of genetic and environmental risk factors leads to the formation of small lipid droplets, likely precursors to retinal drusen, which can be an early sign of macular degeneration. Three cholesterol-inhibiting drugs were found to reduce the formation of lipid droplets in retinal cells grown in a lab setting.
Where: La Cunza N et al., Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration, JCI Insight, 2021.
BrightFocus Connection: This work was partially funded through a 2015-17 BrightFocus Macular Degeneration Research (MDR) grant (the Charlotte and Alexander Danilevsky Memorial Award) to Aparna Lakkaraju, PhD, senior author of this paper and professor of ophthalmology at the University of California, San Francisco, and Kimberly A. Toops, PhD, a co-author on this paper, who was a co-principal investigator with her on that grant at the University of Wisconsin-Madison. In addition, Dr. Lakkaraju had a previous MDR grant (listed below). This year she was awarded the 2021 BrightFocus MDR Innovative Award.
Why It Is Important: While not a genetically inherited disease, age-related macular degeneration (AMD) has been associated with variations in over 50 independent genes. However, links between these genetic risk factors and the underlying biology of the disease are poorly understood. These scientists have provided some answers about how AMD-associated variants promote RPE injury and drusen formation.
Individuals with the ApoE2 allele, a gene variation affecting the cholesterol transport protein ApoE, are at increased risk for developing AMD, but the reason for this genetic association with disease risk is unknown. (In an interesting connection between mind and sight, the different ApoE alleles also are associated with a differing, and in some cases opposite, risk of developing Alzheimer’s disease.) In this study, investigators found that retinal pigment epithelium (RPE) cells with the ApoE2 allele are defective in how they transport cholesterol between cells. RPE cells make up tissue that supports photoreceptors (i.e., the nerve cells that respond to light).
When the ApoE2-mediated transport defect is combined with other biological stressors that activate the immune system (things like age and smoking), the mitochondria become injured and initiate a biochemical cascade that results in the formation of lipid droplets. These droplets are likely precursors to drusen, a major risk factor for AMD disease progression.
The researchers used live-cell imaging to track cellular activity in RPE cells grown in a “dish” model. RPE cells with the ApoE2 allele showed defective transport of cholesterol within the cell. The ApoE2 transport defect rendered the RPE cell vulnerable to attack by inflammatory proteins, which circulate in the blood-seeking out invading pathogens to destroy but do not typically attack healthy cells.
These attacking proteins damaged the mitochondria within ApoE2 RPE cells, causing them to fragment, while the ApoE2 protein condensed into small lipid droplets within the cell, a process known as phase separation. These droplets may be precursors to drusen, thus representing an early step on the pathway towards AMD.
The researchers tested three cholesterol-inhibiting drugs in RPE cells containing the ApoE2 allele. All three drugs decreased injury to the mitochondria and reduced the formation of lipid droplets. The most effective drug was desipramine, which inhibits an enzyme that is activated by excess cholesterol.
This study lays important groundwork for understanding how drusen are formed and developing new approaches to prevent this early development in AMD.
- Aparna Lakkaraju 2021-24 MDR Innovative grant (Lorraine Maresca Award)
- Aparna Lakkaraju and Kimberly Toops 2015-17 MDR grant (Charlotte & Alexander Danilevsky Memorial Award)
- Aparna Lakkaraju 2009-13 MDR grant
- BrightFocus interview with Dr. Lakkaraju (2019)
- Retinal Pigment Epithelium: The Eye’s First Line of Defense Against Macular Degeneration (Science News, 2016)
- Can RPE-Derived Exosomes Contribute to Subretinal Drusenoid Deposits? (Science News, 2015)