Description
The retinal pigment epithelium (RPE) is essential to photoreceptor homeostasis and visual function. Daily RPE phagocytosis of photoreceptor outer segment tips (OS) is essential for photoreceptor renewal following photooxidative damage. Impaired degradation of phagocytosed OS in the RPE leads to accumulation of lipid-rich lipofuscin and RPE degeneration in the common vision-loss disease Age-related Macular Degeneration (AMD). The complexity of genetic and environmental risk factors makes AMD difficult to model, but the accumulation of poorly digested, lipid-rich material is an early hallmark shared by lysosomal storage diseases including Niemann-Pick disease type C (NPC). Mouse models of NPC bare AMD hallmarks including lipofuscin accumulation, photoreceptor degeneration and vision loss, demonstrating the potential value of NPC for studying lipid storage in AMD. Our lab has identified a fusion defect between OS-containing phagosomes and lysosomes in NPC models as well as aberrant membrane contact sites (MCS), where organelles are tethered together in close apposition, resulting in dysregulated inter-organelle communication.
ER contact sites with phagocytic and endocytic organelles provide platforms for lipid and ion exchange and are implicated in maturation of endocytic and phagocytic pathways and in lysosomal calcium signalling, known to be important for lysosomal fusion. However, the role of MCS in phagosome maturation and phagolysosome fusion in the RPE has not been investigated.
The aims of my project are to characterise the role of MCS in phagosome maturation and lysosome fusion in the RPE and to identify compounds that can reverse defective phagosome-lysosome fusion in NPC as potential therapeutic candidates for AMD.
Lay Abstract
The retinal pigment epithelium (RPE) is a layer of cells at the back of the eye that is essential for healthy vision. One of its key roles is to clear and recycle waste from light-detecting cells called photoreceptors, allowing them to function properly. As we age, this recycling process becomes less efficient. Waste material can build up in the RPE, contributing to age-related macular degeneration (AMD), the most common cause of vision loss in adults.
Studying AMD is challenging because it is influenced by many genetic and environmental factors. However, a rare disease called Niemann-Pick type C (NPC) shows similar problems with waste buildup. By studying NPC, we can better understand what goes wrong in AMD. Our research has found that in these conditions, the photoreceptor waste is not properly delivered to the compartment in the RPE where digestion takes place, preventing effective clearance. We think that the way these compartments physically interact is disrupted.
My project aims to identify where this process breaks down in the RPE and to find drugs that can restore normal recycling. This could lead to new treatments to slow or prevent vision loss in AMD.
| Lay Title | How Cells Process Waste in the Eye—and What Goes Wrong in Disease |
|---|---|
| Role | PhD Student |