scholarly journals Reduced Disc Shedding and Phagocytosis of Photoreceptor Outer Segment Contributes to Kava Kava Extract–induced Retinal Degeneration in F344/N Rats

2018 ◽  
Vol 46 (5) ◽  
pp. 564-573 ◽  
Author(s):  
Haruhiro Yamashita ◽  
Mark J. Hoenerhoff ◽  
Keith R. Shockley ◽  
Shyamal D. Peddada ◽  
Kevin E. Gerrish ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Morphological Alteration ◽  
Albino Rats ◽  
Photoreceptor Outer Segment ◽  
Photoreceptor Layer ◽  
Epithelial Homeostasis ◽  
Kava Kava

There was a significant increase in the incidence of retinal degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced retinal degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced retinal degeneration. To investigate the early mechanism of retinal degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced retinal degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of retinal degeneration observed in F344/N rats in the 2-year KKE bioassay.

scholarly journals Light-induced Oxidation of Photoreceptor Outer Segment Phospholipids Generates Ligands for CD36-mediated Phagocytosis by Retinal Pigment Epithelium

2006 ◽  
Vol 281 (7) ◽  
pp. 4222-4230 ◽  
Author(s):  
Mingjiang Sun ◽  
Silvia C. Finnemann ◽  
Maria Febbraio ◽  
Lian Shan ◽  
Suresh P. Annangudi ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Photoreceptor Outer Segment

scholarly journals Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 771 ◽  
Author(s):  
Marci L. DeRamus ◽  
Stephanie J. Davis ◽  
Sriganesh Ramachandra Rao ◽  
Cyril Nyankerh ◽  
Delores Stacks ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Types ◽  
Protein Glycosylation ◽  
Photoreceptor Layer ◽  
Selective Ablation ◽  
Rpe Atrophy ◽  
Structural Loss

Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhddsflx/flx). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation.

scholarly journals PRCD is essential for high-fidelity photoreceptor disc formation

2019 ◽  
Vol 116 (26) ◽  
pp. 13087-13096 ◽  
Author(s):  
William J. Spencer ◽  
Jin-Dong Ding ◽  
Tylor R. Lewis ◽  
Chen Yu ◽  
Sebastien Phan ◽  
...  
Keyword(s):  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
High Fidelity ◽  
Photoreceptor Outer Segment ◽  
Progressive Degeneration ◽  
Microglial Migration ◽  
Microglial Response ◽  
Interphotoreceptor Matrix ◽  
Disc Formation

Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor’s ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.

scholarly journals Kif17 phosphorylation regulates its ciliary localization and photoreceptor outer segment turnover

2018 ◽  
Author(s):  
Tylor R. Lewis ◽  
Sean R. Kundinger ◽  
Brian A. Link ◽  
Christine Insinna ◽  
Joseph C. Besharse
Keyword(s):  
Mammalian Cells ◽  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Consensus Sequence ◽  
Intraflagellar Transport ◽  
Photoreceptor Outer Segment ◽  
Transgenic Expression ◽  
Outer Segments ◽  
Ciliary Localization

AbstractBackgroundKIF17, a kinesin-2 motor that functions in intraflagellar transport, can regulate the onset of photoreceptor outer segment development. However, the function of KIF17 in a mature photoreceptor remains unclear. Additionally, the ciliary localization of KIF17 is regulated by a C-terminal consensus sequence (KRKK) that is immediately adjacent to a conserved residue (mouse S1029/zebrafish S815) previously shown to be phosphorylated by CaMKII. Yet, whether this phosphorylation can regulate the localization, and thus function, of KIF17 in ciliary photoreceptors remains unknown.ResultsUsing transgenic expression in both mammalian cells and zebrafish photoreceptors, we show that phospho-mimetic KIF17 has enhanced localization to cilia. Importantly, expression of phospho-mimetic KIF17 is associated with greatly enhanced turnover of the photoreceptor outer segment through disc shedding in a cell-autonomous manner, while genetic mutants of kif17 in zebrafish and mice have diminished disc shedding. Lastly, cone expression of constitutively active tCaMKII leads to a kif17-dependent increase in disc shedding.ConclusionsTaken together, our data support a model in which phosphorylation of KIF17 promotes its ciliary localization. In cone photoreceptor outer segments, this promotes disc shedding, a process essential for photoreceptor maintenance and homeostasis. While disc shedding has been predominantly studied in the context of the mechanisms underlying phagocytosis of outer segments by the retinal pigment epithelium, this work implicates photoreceptor-derived signaling in the underlying mechanisms of disc shedding.

scholarly journals Fast voltage sensitivity in retinal pigment epithelium: sodium channels and their novel role in phagocytosis

2017 ◽  
Author(s):  
Julia K. Johansson ◽  
Teemu O. Ihalainen ◽  
Heli Skottman ◽  
Soile Nymark
Keyword(s):  
Retinal Pigment Epithelium ◽  
Sodium Channels ◽  
Connexin 43 ◽  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Junctions ◽  
Voltage Sensitivity ◽  
Photoreceptor Outer Segment ◽  
Junction Protein

AbstractDespite the discoveries of voltage-gated sodium channels (Nav) from a number of non-excitable cell types, the presence of Nav-mediated currents in cells of the retinal pigment epithelium (RPE) has been dismissed as a cell culture artifact. Here, we challenge this notion by demonstrating functional Nav1.4-Nav1.6 and Nav1.8 channels in human embryonic stem cell derived and mouse RPE. Importantly, we show that Navs are involved in photoreceptor outer segment phagocytosis: blocking their activity significantly reduces the efficiency of this process. Consistent with this role, Nav1.8 co-localizes with the endosomal marker Rab7 and, during phagocytosis, with opsin. Nav1.4 localizes strongly to the cell-cell junctions together with the gap junction protein Connexin 43. During phagocytosis, both are localized to the phagosomes with a concurrent decrease in the junctional localization. Our study demonstrates that Navs give the capacity of fast electrical signaling to RPE and that Navs play a novel role in photoreceptor outer segment phagocytosis.

EM immunocytochemical localization of rhodopsin and IRBP during retinal development

1989 ◽  
Vol 47 ◽  
pp. 800-801
Author(s):  
R. J. Ulshafer ◽  
W.W. Hauswirth ◽  
A. van der Langerijt
Keyword(s):  
Outer Segment ◽  
Electrical Response ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Rabbit Serum ◽  
Subretinal Space ◽  
Rod Photoreceptor ◽  
Photoreceptor Outer Segment ◽  
Thin Sections ◽  
Specific Proteins

Two rod photoreceptor cell-specific proteins, rhodopsin and interphotoreceptor retinoid binding protein (IRBP), were localized during fetal development of the bovine retina using immuncicrytcichemistry. Rhodopsin is the light sensitive protein that, when activated, begins the process of transducing light energy to an electrical response. IRBP is a carrier protein that shuttles light-isomerized vitamin A (retinol) between the rod outer segment and the overlying retinal pigment epithelium where it is recycled to its light-sensitive form. Rhodopsin has been previously imimmocytochemically localized to rod (but not cone) photoreceptor outer segment membranes. IRBP has been localized to the subretinal space using immunocytochemistry.Retinas were obtained from fetuses at approximately 4, 5, 6, 7, and 8 months of gestation, fixed in 4% paraformaldehyde and 0.5% glutaraldehyde, and embedded at 40°C in epoxy resin. Thin sections were mounted on Ni grids and incubated with antibodies raised against the purified antigens: a mouse monoclonal anti-rhodopsin or a rabbit polyclonal anti-IRBP. A second antibody (Goat-anti-mouse or Goat-anti-rabbit) was conjugated with 15 nm Au particles and reacted with the sections. Control incubations were made using pre-immune rabbit serum and mouse monoclonals made against other tissue or bacterial sources.

scholarly journals Defective phagosome motility and degradation in cell nonautonomous RPE pathogenesis of a dominant macular degeneration

2018 ◽  
Vol 115 (21) ◽  
pp. 5468-5473 ◽  
Author(s):  
Julian Esteve-Rudd ◽  
Roni A. Hazim ◽  
Tanja Diemer ◽  
Antonio E. Paniagua ◽  
Stefanie Volland ◽  
...  
Keyword(s):  
Outer Segment ◽  
Photoreceptor Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Loss ◽  
Neural Retina ◽  
Macular Dystrophy ◽  
Wild Type ◽  
Photoreceptor Outer Segment ◽  
And Oxidative Stress

Stargardt macular dystrophy 3 (STGD3) is caused by dominant mutations in the ELOVL4 gene. Like other macular degenerations, pathogenesis within the retinal pigment epithelium (RPE) appears to contribute to the loss of photoreceptors from the central retina. However, the RPE does not express ELOVL4, suggesting photoreceptor cell loss in STGD3 occurs through two cell nonautonomous events: mutant photoreceptors first affect RPE cell pathogenesis, and then, second, RPE dysfunction leads to photoreceptor cell death. Here, we have investigated how the RPE pathology occurs, using a STGD3 mouse model in which mutant human ELOVL4 is expressed in the photoreceptors. We found that the mutant protein was aberrantly localized to the photoreceptor outer segment (POS), and that resulting POS phagosomes were degraded more slowly in the RPE. In cell culture, the mutant POSs are ingested by primary RPE cells normally, but the phagosomes are processed inefficiently, even by wild-type RPE. The mutant phagosomes excessively sequester RAB7A and dynein, and have impaired motility. We propose that the abnormal presence of ELOVL4 protein in POSs results in phagosomes that are defective in recruiting appropriate motor protein linkers, thus contributing to slower degradation because their altered motility results in slower basal migration and fewer productive encounters with endolysosomes. In the transgenic mouse retinas, the RPE accumulated abnormal-looking phagosomes and oxidative stress adducts; these pathological changes were followed by pathology in the neural retina. Our results indicate inefficient phagosome degradation as a key component of the first cell nonautonomous event underlying retinal degeneration due to mutant ELOVL4.

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