New Discovery on Retinal Gene Points to Age-Related Vision Loss and Potential Treatments

Medical News: A recent study from researchers at Vanderbilt University Medical Center-USA is shedding light on how a specific gene, Prominin-1 (Prom1), may play a critical role in retinal degeneration. This discovery could pave the way for new treatments to combat atrophic age-related macular degeneration (aAMD), an irreversible form of vision loss affecting millions worldwide. Led by Sujoy Bhattacharya, Tzushan Sharon Yang, Bretton P. Nabit, Evan S. Krystofiak, Tonia S. Rex, and Edward Chaum, this study focuses on the function of Prom1 in maintaining the health of the retinal pigment epithelium (RPE), a cell layer vital to vision.


New Discovery on Retinal Gene Points to Age-Related Vision Loss and Potential Treatments

The Importance of Prom1 in Retinal Health
The Prom1 gene, known for its association with stem cell differentiation and photoreceptor (light-sensing cell) health, was tested in mouse models to understand its impact on RPE cells. Located within the eye's retina, the RPE cells support the photoreceptors by supplying nutrients, managing waste, and absorbing stray light. When these cells degenerate, as they do in aAMD, vision loss becomes inevitable. In this Medical News report, we will delve into how Prom1 supports the RPE and what its dysfunction means for retinal health.
 
Prom1 is notably present in photoreceptors and, as the researchers discovered, is crucial in regulating cellular processes such as autophagy (cell recycling) and cellular homeostasis. Autophagy allows cells to clear out damaged components, thus preventing cell death. The researchers identified that Prom1 is expressed in specific regions within RPE cells, particularly around cellular components like mitochondria, which are essential for cell energy production.
 
Methodology and Experiments on Mice
To better understand Prom1's function in RPE cells, the Vanderbilt team employed RNAscope assays and immunogold electron microscopy to observe Prom1 in mouse retinas. They used chromogenic and fluorescent probes, allowing them to trace the gene's activity precisely in the RPE. Additionally, the researchers utilized AAV2/1 viral vectors to specifically knock down the Prom1 gene in the RPE cells of live mice. This approach enabled them to observe how the lack of Prom1 affected the cellular structure and function of the RPE over time.
 
The study also utilized single-cell RNA sequencing, focusing on sub-populations of RPE cells from both human and mouse sources. The data were cross-referenced with human cell clusters using Spectacle, a tool designed to identify gene expression patterns within specific cell types.
 
Findings Reveal Prom1's Role in Cellular Homeostasis and Autophagy
The findings highlighted that Prom1 is essential in maintaining RPE structure, influencing autophagy regulation. Mice with Prom1 knocked down exhibited abnormal RPE morphology, fluid accumulation beneath the retina, and eventual photoreceptor loss. The loss of Prom1 triggered a series of degenerative processes, ultimately r esulting in cellular death in RPE cells.
 
Researchers discovered that knocking down Prom1 led to abnormal formation and shape of RPE cells. This abnormality created "patchy" cell death in the RPE layer, which interfered with the retina's overall health. The absence of Prom1 also disrupted autophagic processes, a vital recycling pathway, causing a buildup of cellular waste that contributed to degeneration.
 
The study showed that even a partial loss of Prom1 in the RPE caused significant structural and functional changes. For instance, affected cells lost their shape, and the clear separation between RPE and the retinal layers was disrupted. Additionally, photoreceptors began to deteriorate, as they rely on a healthy RPE layer to receive nutrients and recycle their cellular waste.
 
Electroretinography and Functional Loss
To measure the functional impact of Prom1 loss on vision, researchers conducted electroretinograms (ERGs) on the mice. ERGs assess the electrical responses of various cell types in the retina when stimulated by light, reflecting the eye's functional capacity. Results indicated that mice with RPE-specific Prom1 knockdown had significantly reduced a-wave amplitudes, indicating impaired photoreceptor function. This loss in functionality was observed as early as 11 weeks after the genetic manipulation, providing a rapid timeline for retinal degeneration.
 
The Role of Microglia and Inflammatory Response
The study also identified a connection between Prom1, retinal health, and immune system responses. Prom1-positive microglial cells (immune cells in the retina) play a role in clearing debris, including dead photoreceptor segments, particularly in damaged areas of the retina. These cells act as "clean-up" agents, keeping the retina free from harmful waste products. When Prom1 expression was reduced, the activity of these microglial cells also changed, potentially worsening the accumulation of cellular waste and further accelerating degeneration.
 
Potential Impact for aAMD Treatments
Given that there is no effective treatment for the progressive vision loss associated with aAMD, understanding Prom1's role could help develop new therapies. Targeting Prom1 or its cellular pathways might be a way to halt or even reverse the damage in RPE cells before they cause photoreceptor death. For instance, treatments could focus on stabilizing Prom1 expression or promoting its function within RPE cells, possibly preserving vision in at-risk individuals.
 
Conclusion
The Vanderbilt team’s study is a breakthrough in understanding how genetic factors like Prom1 contribute to retinal diseases, particularly aAMD. Prom1 is essential for RPE cell maintenance and autophagic balance, which in turn protects photoreceptors. This research underscores how even a slight genetic imbalance can start a cascade of degenerative changes in the retina, illustrating the fragility and interconnectedness of cellular systems in the eye.
 
Looking ahead, this research could lead to potential therapies aimed at stabilizing Prom1 or activating its pathways in retinal cells. While further studies are required, this promising avenue offers hope for millions facing irreversible vision loss. This study opens new doors for research into treatments that could one day stop or reverse age-related vision decline.
 
The study findings were published in the peer-reviewed journal: Cells.
https://www.mdpi.com/2073-4409/13/21/1761
 
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