Contribution of Microglia and Müller Cells to Retinal Degeneration Due to MerTk Deficiency
Retinitis Pigmentosa (RP) is a group of inherited retinal degenerative diseases that lead patients to progressively lose peripheral photoreceptors resulting in total blindness usually at about 40 years of age. One of the most severe forms of RP is due to mutations in the gene MERTK, encoding a receptor tyrosine kinase. Patients with MERTK mutations experience symptoms already in early childhood and progress to complete blindness by about 15 years of age. It was the goal of my thesis research to determine the cellular–physiological mechanisms that underlie the early onset and rapid progression of retinal degeneration in MerTK related RP.In the eye, MerTK receptors of the RPE are required for the daily renewal of photoreceptor outer segments allowing the life-long maintenance of a healthy, functional retina. This process is essential for vision and involves many other genes and their protein products in addition to MerTK. However, only mutations in MERTK lead to early onset RP. Although its role in photoreceptor renewal is well understood, it is still unknown whymutations in this gene cause such devastating blinding disease, which unfortunately has no cure or therapy available to date.In my studies, I focused on approaches to delay the retinal degeneration. I found that inflammation through the activation of microglia, and potentially Müller cells are aggravating the retinal degeneration. By reducing microglia activity, I was able to successfully delay the retinal degeneration and improve visual acuity in models animals.Additionally, I showed that galectin-3 plays an important neuroprotective role in the degenerating retina. Lack of galectin-3 worsens retinal degeneration in both a model of inherited degeneration and a model of chemically induced degeneration. While underlying mechanisms still need unravelling, my results suggest that galectin-3 likely acts by modulating the activation/proliferation and potentially phagocytic activities of retinal inflammatory cells such as microglia and Müller cells.Interestingly, I found that Müller cells like RPE cells express MerTK receptors. Moreover, I have shown that Müller cells were able to use Protein S and galectin-3 as ligands for MerTK receptor to mediate clearance phagocytosis. These results suggest that the loss of MerTK-dependent phagocytosis by Müller cells could also contribute to the rapid onset of retinal degeneration due to MerTK deficiency.Altogether, my results reveal that both microglia and Müller cells are important players whose activities in part via galectin-3 affect the outcome of Retinitis Pigmentosa and other forms of retinal degeneration. Therefore, these cells should strongly be considered as potential targets for future therapy aiming at delaying retinal degeneration.
Cellular biology|Genetics|Molecular biology|Ophthalmology
Lew, Deborah Sarah, "Contribution of Microglia and Müller Cells to Retinal Degeneration Due to MerTk Deficiency" (2021). ETD Collection for Fordham University. AAI28492412.