Molecular basis for photoreceptor outer segment architecture

To serve vision, vertebrate rod and cone photoreceptors must detect photons, convert the light stimuli into cellular signals, and then convey the encoded information to downstream neurons. Rods and cones are sensory neurons that each rely on specialized ciliary organelles to detect light. These organelles, called outer segments, possess elaborate architectures that include many hundreds of light-sensitive membranous disks arrayed one atop another in precise register. These stacked disks capture light and initiate the chain of molecular and cellular events that underlie normal vision. Outer segment organization is challenged by an inherently dynamic nature; these organelles are subject to a renewal process that replaces a significant fraction of their disks (up to ∼10%) on a daily basis. In addition, a broad range of environmental and genetic insults can disrupt outer segment morphology to impair photoreceptor function and viability. In this chapter, we survey the major progress that has been made for understanding the molecular basis of outer segment architecture. We also discuss key aspects of organelle lipid and protein composition, and highlight distributions, interactions, and potential structural functions of key OS-resident molecules, including: kinesin-2, actin, RP1, prominin-1, protocadherin 21, peripherin-2/rds, rom-1, glutamic acid-rich proteins, and rhodopsin. Finally, we identify key knowledge gaps and challenges that remain for understanding how normal outer segment architecture is established and maintained.     

Roles of exosomes in the normal and diseased eye

Exosomes are nanometer-sized vesicles that are released by cells in a controlled fashion and mediate a plethora of extra- and intercellular activities. Some key functions of exosomes include cell-cell communication, immune modulation, extracellular matrix turnover, stem cell division/differentiation, neovascularization and cellular waste removal. While much is known about their role in cancer, exosome function in the many specialized tissues of the eye is just beginning to undergo rigorous study. Here we review current knowledge of exosome function in the visual system in the context of larger bodies of data from other fields, in both health and disease. Additionally, we discuss recent advances in the exosome field including use of exosomes as a therapeutic vehicle, exosomes as a source of biomarkers for disease, plus current standards for isolation and validation of exosome populations. Finally, we use this foundational information about exosomes in the eye as a platform to identify areas of opportunity for future research studies.     

Improving our understanding,and detection,of glaucomatous damage: An approach based upon optical coherence tomography (OCT)

Although ophthalmologists are becoming increasingly reliant upon optical coherence tomography (OCT), clinicians who care for glaucoma patients are not taking full advantage of the potential of this powerful technology. First, we ask, how would one describe the nature of glaucomatous damage if only OCT scans were available? In particular, a schematic model of glaucomatous damage is developed in section 2, and the nature of glaucomatous damage seen on OCT scans described in the context of this model in section 3. In particular, we illustrate that local thinning of the circumpapillary retinal nerve fiber layer (cpRNFL) around the optic disc can vary in location, depth, and/or width, as well as homogeneity of damage. Second, we seek to better understand the relationship between the thinning of the cpRNFL and the various patterns of sensitivity loss seen on visual fields obtained with standard automated perimetry. In sections 4 and 5, we illustrate why one should expect a wide range of visual field patterns, and iilustrate why they should not be placed into discrete categories. Finally, section 6 describes how the clinician can take better advantage of the information in OCT scans. The approach is summarized in a single-page report, which can be generated from a single wide-field scan. The superiority of this approach, as opposed to the typical reliance on summary metrics, is described.     

Autophagy in the eye: Development,degeneration, and aging

Autophagy is a catabolic pathway that promotes the degradation and recycling of cellular components. Proteins, lipids, and even whole organelles are engulfed in autophagosomes and delivered to the lysosome for elimination. In response to stress, autophagy mediates the degradation of cell components, which are recycled to generate the nutrients and building blocks required to sustain cellular homeostasis. Moreover, it plays an important role in cellular quality control, particularly in neurons, in which the total burden of altered proteins and damaged organelles cannot be reduced by redistribution to daughter cells through cell division. Research has only begun to examine the role of autophagy in the visual system. The retina, a light-sensitive tissue, detects and transmits electrical impulses through the optic nerve to the visual cortex in the brain. Both the retina and the eye are exposed to a variety of environmental insults and stressors, including genetic mutations and age-associated alterations that impair their function. Here, we review the main studies that have sought to explain autophagy's importance in visual function. We describe the role of autophagy in retinal development and cell differentiation, and discuss the implications of autophagy dysregulation both in physiological aging and in important diseases such as age-associated macular degeneration and glaucoma. We also address the putative role of autophagy in promoting photoreceptor survival and discuss how selective autophagy could provide alternative means of protecting retinal cells. The findings reviewed here underscore the important role of autophagy in maintaining proper retinal function and highlight novel therapeutic approaches for blindness and other diseases of the eye.     

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments.