Basal C1QTNF5-S163R Mutant Deposits and Drusen Formation: Implications for AMD
Age-related macular degeneration (AMD) is characterized by the presence of drusen, abnormal extracellular deposits composed of protein and lipids that accumulate between the RPE and choroid, the layer of blood vessels providing oxygen and nutrients to the RPE. Our goal is to understand the factors contributing to the formation of drusen deposits, in order to develop a strategy to eliminate them and preserve vision in AMD patients.
Extracellular deposits that accumulate within the RPE/choroid interface, such as drusen and basal laminar and linear deposits, are central to the pathogenesis and severity of AMD. These deposits may block the transport of oxygen and nutrients to the RPE and photoreceptor cells, causing vision loss.The main objective of our research project is to understand the cellular and molecular mechanisms that contribute to the formation of drusen deposits in dry AMD, in order to develop therapeutic approaches for this disorder and prevent vision loss. However, AMD is a complex disorder caused by an interplay of many environmental and genetic risk factors. In contrast, a disease known as late-onset retinal degeneration has a well understood genetic cause, and shares several key features with AMD, including the presence of characteristic drusen-like deposits similar to those found in patients with AMD. L-ORD is caused by the S163R mutation in complement C1QTNF5 protein, which is highly expressed in the RPE. To date, the biological function of C1QTNF5 in the RPE is unknown. We have previously shown that overexpression of mutant S163R C1QTNF5 protein in murine RPE leads to the formation of thick, extracellular RPE basal deposits and regions of RPE atrophy. Therefore, our specific aims are centered on understanding the roles of C1QTNF5 protein in the eye, the identification of its binding partners, and the factors contributing to the formation of RPE extracellular deposits. This will allow us to also understand the mechanisms contributing to the RPE dysfunction and the biogenesis of the more complex drusen deposits in AMD patients.
About the Researcher
Astra Dinculescu, PhD, is assistant professor in the Department of Ophthalmology at the University of Florida, College of Medicine. She completed her doctoral studies in the Department of Biochemistry at the University of Florida, where she focused on proteins involved in signaling pathways within photoreceptor cells, the neurons responsible for vision. During her postdoctoral training, she studied several naturally occurring mouse models of inherited recessive retinal disorders, and successfully developed gene-based therapeutic strategies to prevent retinal degeneration and restore retinal function in these models. Her laboratory focuses on understanding the cellular and molecular mechanisms leading to photoreceptor cell death in retinal degenerative disorders, including AMD, in order to develop therapeutic strategies to prevent vision loss.
Ever since I started my career in vision, I have been fascinated by the interplay between the retinal pigment epithelium cells (RPE) and the light-sensing neurons in the retina, the photoreceptors. The RPE cells extend numerous long finger-like projections which surround the essential light-capturing photoreceptors, constantly bringing oxygen and nutrients to them, and removing the waste products. Without healthy RPE cells, photoreceptors ultimately die and can never be replaced, and patients permanently lose vision. This irreversible and devastating process that patients with macular degeneration are facing motivated me to pursue answers to fundamental questions: Why do RPE cells become particularly vulnerable during aging? How is the waste material eliminated from the RPE? And how does the debris known as drusen accumulate as thick deposits under the RPE cells in AMD? What is the origin of the drusen deposit and its impact on the loss of vision in AMD patients? What are the strategies to prevent and eliminate these deposits? The trust and generous support from the BrightFocus Foundation and its donors will enable me and other researchers to find answers to these questions and ultimately develop efficient strategies against AMD to prevent the loss of vision.
First published on: August 7, 2017
Last modified on: August 17, 2019