Abstract: The retinal degenerative diseases retinitis pigmentosa and age-related macular degeneration are a leading cause of irreversible vision loss. Both present with progressive photoreceptor degeneration that is further complicated by processes of retinal remodeling. In this perspective, we discuss the current state of the field of retinal remodeling and its implications for vision-restoring therapeutics currently in development. Here, we discuss the challenges and pitfalls retinal remodeling poses for each therapeutic strategy under the premise that understanding the features of retinal remodeling in totality will provide a basic framework with which therapeutics can interface. Additionally, we discuss the potential for approaching therapeutics using a combined strategy of using diffusible molecules in tandem with other vision-restoring therapeutics. We end by discussing the potential of the retina and retinal remodeling as a model system for more broadly understanding the progression of neurodegeneration across the central nervous system.
We have a new manuscript out in Experimental Eye Research, Model-Based Comparison of Current Flow in Rod Bipolar Cells of Healthy and Early-Stage Degenerated Retina. (pdf here)
Authors: Pragya Kosta, Ege Iseri, Kyle Loizos, Javad Paknahad, Rebecca L. Pfeiffer @BeccaPfeiffer19, Crystal L. Sigulinsky @CLSigulinsky, James R. Anderson, Bryan W. Jones @BWJones, and Gianluca Lazzi.
Abstract: Retinal degenerative diseases, such as retinitis pigmentosa, are generally thought to initiate with the loss of photoreceptors, though recent work suggests that plasticity and remodeling occurs prior to photoreceptor cell loss. This degeneration subsequently leads to death of other retinal neurons, creating functional alterations and extensive remodeling of retinal networks. Retinal prosthetic devices stimulate the surviving retinal cells by applying external current using implanted electrodes. Although these devices restore partial vision, the quality of restored vision is limited. Further knowledge about the precise changes in degenerated retina as the disease progresses is essential to understand how current flows in retinas undergoing degenerative disease and to improve the performance of retinal prostheses. We developed computational models that describe current flow from rod photoreceptors to rod bipolar cells
We have a new manuscript out in Progress In Retinal And Eye Research, Persistent Remodeling And Neurodegeneration In Late-Stage Retinal Degeneration.
I’m really proud of the work that Becca did on this manuscript. It does a couple of important things including summarizing the field of retinal remodeling, but also introducing some new data that plants a flag to define retinal degeneration and retinal remodeling as the first steps in what becomes progressive neurodegeneration. We view the retina as an excellent model to begin exploring diseases like Alzheimer’s, Parkinson’s, and other progressive neurodegenerative diseases. In addition, Becca also demonstrates a new potential mechanism for misfolded proteins, that may point the way for how proteinopathies spread.
Abstract: Retinal remodeling is a progressive series of negative plasticity revisions that arise from retinal degeneration, and are seen in retinitis pigmentosa, age-related macular degeneration and other forms of retinal disease. These processes occur regardless of the precipitating event leading to degeneration. Retinal remodeling then culminates in a late-stage neurodegeneration that is indistinguishable from progressive central nervous system (CNS) proteinopathies. Following long-term deafferentation from photoreceptor cell death in humans, and long-lived animal models of retinal degeneration, most retinal neurons reprogram, then die. Glial cells reprogram into multiple anomalous metabolic phenotypes. At the same time, survivor neurons display degenerative inclusions that appear identical to progressive CNS neurodegenerative disease, and contain aberrant α-synuclein (α-syn) and phosphorylated α-syn. In addition, ultrastructural analysis indicates a novel potential mechanism for misfolded protein transfer that may explain how proteinopathies spread. While neurodegeneration poses a barrier to prospective retinal interventions that target primary photoreceptor loss, understanding the progression and time-course of retinal remodeling will be essential for the establishment of windows of therapeutic intervention and appropriate tuning and design of interventions. Finally, the development of protein aggregates and widespread neurodegeneration in numerous retinal degenerative diseases positions the retina as a ideal platform for the study of proteinopathies, and mechanisms of neurodegeneration that drive devastating CNS diseases.