Cone photoreceptor dysfunction in retinitis pigmentosa revealed by optoretinography

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength–sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength–sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.

A Vision-Saving Straw in a Retinitis Pigmentosa Patient

We report a case of binocular retinitis pigmentosa (RP) with completely different visual acuity between 2 eyes, which may be contributed by the presence of cilioretinal arteries (CRAs) in 1 eye. A 66-year-old female patient complained of blurred vision after binocular cataract surgeries. Examinations revealed her right eye had 20/25 central visual acuity, but the fellow eye only had light perception. Subsequent fundus photography of both eyes firmed the diagnosis of binocular RP. However, there were some significant differences in retinal vessels, which were attenuated in her left eye in contrast to several spared retinal arterioles in the right eye. Optical coherence tomography angiography showed that the spared vessels might be CRAs. Our case provides an evidence that macular blood flow may contribute to the survival of cone cells in RP.

Gypenosides Alleviate Cone Cell Death in a Zebrafish Model of Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of visual disorders caused by mutations in over 70 genes. RP is characterized by initial degeneration of rod cells and late cone cell death, regardless of genetic abnormality. Rod cells are the main consumers of oxygen in the retina, and after the death of rod cells, the cone cells have to endure high levels of oxygen, which in turn leads to oxidative damage and cone degeneration. Gypenosides (Gyp) are major dammarane-type saponins of Gynostemma pentaphyllum that are known to reduce oxidative stress and inflammation. In this project we assessed the protective effect of Gyp against cone cell death in the rpgrip1 mutant zebrafish, which recapitulate the classical pathological features found in RP patients. Rpgrip1 mutant zebrafish were treated with Gyp (50 µg/g body weight) from two-months post fertilization (mpf) until 6 mpf. Gyp treatment resulted in a significant decrease in cone cell death compared to that of untreated mutant zebrafish. A markedly low level of reactive oxygen species and increased expression of antioxidant genes were detected in Gyp-incubated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Similarly, the activities of catalase and superoxide dismutase and the level of glutathione were significantly increased in Gyp-treated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Gyp treatment also decreased endoplasmic reticulum stress in rpgrip1 mutant eyes. Expression of proinflammatory cytokines was also significantly decreased in Gyp-treated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Network pharmacology analysis demonstrated that the promotion of cone cell survival by Gyp is possibly mediated by multiple hub genes and associated signalling pathways. These data suggest treatment with Gyp will benefit RP patients.

Subcellular localization of PKA catalytic subunits provides a basis for their distinct functions in the retina

PKA signaling is essential for numerous processes but the subcellular localization of specific PKA isoforms has yet to be explored comprehensively in tissues. Expression of the Cβ protein, in particular, has not been mapped previously at the tissue level. In this study we used retina as a window into PKA signaling in the brain and characterized localization of PKA Cα, Cβ, RIIα, and RIIβ subunits. Each subunit presented a distinct localization pattern. Cα and Cβ were localized in all tissue layers, while RIIα and RIIβ were enriched in the photoreceptor cells in contrast to the cell body and retinal portion of retinal ganglion cells. Only Cα was observed in photoreceptor outer segments and the cilia transition zone, while Cβ was localized primarily to mitochondria and was especially prominent in the ellipsoid of the cone cells. In contrast to Cα, Cβ also never colocalized with RIIα or RIIβ. Using BaseScope technology to track expression of the Cβ isoforms we find that Cβ4 and Cβ4ab are prominently expressed and, therefore, likely code for mitochondrial-Cβ proteins. Our data indicates that PKA subunits are functionally nonredundant in the retina and suggesting that Cβ might be important for mitochondrial-associated neurodegenerative diseases previously linked to PKA dysfunction.

A combination of notch signaling, preferential adhesion and endocytosis induces a slow mode of cell intercalation in the Drosophila retina

Movement of epithelial cells in a tissue occurs through neighbor exchange and drives tissue shape changes. It requires intercellular junction remodeling, a process typically powered by the contractile actomyosin cytoskeleton. This has mostly been investigated in homogeneous epithelia where intercalation takes minutes. However, in some tissues, intercalation involves different cell types and can take hours. Whether slow and fast intercalation share the same mechanisms remains to be examined. To address this issue, we use the fly eye, where the cone cells exchange neighbors over approximately 10 hours to shape the lens. We uncover three pathways regulating this slow mode of cell intercalation. Firstly, we find a limited requirement for MyosinII. In this case, mathematical modeling predicts an adhesion dominant intercalation mechanism. Genetic experiments support this prediction and reveal a role for adhesion through the Nephrin proteins Roughest and Hibris. Secondly, we find cone cell intercalation is regulated by the Notch-signaling pathway. Thirdly, we show endocytosis is required for membrane removal and Notch activation. Altogether, our work indicates that adhesion, endocytosis and Notch can induce junction remodeling over long-time scales.

Dyschromatopsy, Achromatopsia and Blue Cone Monochromatism; Pathophysiology, Clinical Findings, Diagnosis, and Treatment

Color vision is a complex perception caused by the stimulation of cone photoreceptors in the retina and the perception of this stimulation in the brain. Hereditary color vision deficiencies are caused by a defect in the functions of cone cells. Color vision deficiencies are named according to three different types of pigments contained in cones. These disorders, which are seen in high prevalence worldwide, are found more frequently in males. Contrary to thought, colored vision defects often affect daily life. Although it can be easily diagnosed with color vision tests and electrophysiological tests, current treatment options are limited and its success rate is low.

Automated Cone Cell Identification on Adaptive Optics Scanning Laser Ophthalmoscope Images Based on TV-L1 Optical Flow Registration and K-Means Clustering

Cone cell identification is essential for diagnosing and studying eye diseases. In this paper, we propose an automated cone cell identification method that involves TV-L1 optical flow estimation and K-means clustering. The proposed algorithm consists of the following steps: image denoising based on TV-L1 optical flow registration, bias field correction, cone cell identification based on K-means clustering, duplicate identification removal, identification based on threshold segmentation, and merging of closed identified cone cells. Compared with manually labelled ground-truth images, the proposed method shows high effectiveness with precision, recall, and F1 scores of 93.10%, 94.97%, and 94.03%, respectively. The method performance is further evaluated on adaptive optics scanning laser ophthalmoscope images obtained from a healthy subject with low cone cell density and subjects with either diabetic retinopathy or acute zonal occult outer retinopathy. The evaluation results demonstrate that the proposed method can accurately identify cone cells in subjects with healthy retinas and retinal diseases.

Human Eye Optics within a Non-Euclidian Geometrical Approach and Some Implications in Vision Prosthetics Design

An analogy with our previously published theory on the ionospheric auroral gyroscope provides a new perspective in human eye optics. Based on cone cells’ real distribution, we model the human eye macula as a pseudospherical surface. This allows the rigorous description of the photoreceptor cell densities in the parafoveal zones modeled further by an optimized paving method. The hexagonal photoreceptors’ distribution has been optimally projected on the elliptical pseudosphere, thus designing a prosthetic array counting almost 7000 pixel points. Thanks to the high morphological similarities to a normal human retina, the visual prosthesis performance in camera-free systems might be significantly improved.