URINARY METABOLOMICS OF CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To analyze the urinary metabolomic profile of central serous chorioretinopathy cases. METHODS: In a cross-sectional study, 80 participants with central serous chorioretinopathy were compared with 80 age-matched and sex-matched controls. Urinary metabolites were measured using Metabolon's Discovery HD4 platform. RESULTS: Of 1,031 metabolites total that were measured in urine samples, 53 were upregulated and 27 downregulated in central serous chorioretinopathy participants compared with controls. After exclusion of potentially confounding xenobiotics and bile compounds that could represent digestive processes, 14 metabolites were significantly higher and 12 metabolites were significantly lower in cases compared with controls. One upregulated metabolite (tetrahydrocortisol sulfate) is involved in the corticosteroid subpathway. The downregulated metabolites are unrelated to the identified corticosteroid subpathway. CONCLUSION: The upregulation of urinary tetrahydrocortisol sulfate in central serous chorioretinopathy cases provides a precise molecular basis to further study the role of corticosteroids in producing choroidal venous congestion.

Characterization and identification of measurable endpoints in a mouse model featuring age-related retinal pathologies: a platform to test therapies.

Apolipoprotein B100 (apoB100) is the structural protein of cholesterol carriers including low-density lipoproteins. It is a constituent of sub-retinal pigment epithelial (sub-RPE) deposits and pro-atherogenic plaques, hallmarks of early dry age-related macular degeneration (AMD), an ocular neurodegenerative blinding disease, and cardiovascular disease, respectively. Herein, we characterized the retinal pathology of transgenic mice expressing mouse apoB100 in order to catalog their functional and morphological ocular phenotypes as a function of age and establish measurable endpoints for their use as a mouse model to test potential therapies. ApoB100 mice were found to exhibit an age-related decline in retinal function, as measured by electroretinogram (ERG) recordings of their scotopic a-wave, scotopic b-wave; and c-wave amplitudes. ApoB100 mice also displayed a buildup of the cholesterol carrier, apolipoprotein E (apoE) within and below the supporting extracellular matrix, Bruch's membrane (BrM), along with BrM thickening, and accumulation of thin diffuse electron-dense sub-RPE deposits, the severity of which increased with age. Moreover, the combination of apoB100 and advanced age were found to be associated with RPE morphological changes and the presence of sub-retinal immune cells as visualized in RPE-choroid flatmounts. Finally, aged apoB100 mice showed higher levels of circulating and ocular pro-inflammatory cytokines, supporting a link between age and increased local and systemic inflammation. Collectively, the data support the use of aged apoB100 mice as a platform to evaluate potential therapies for retinal degeneration, specifically drugs intended to target removal of lipids from Bruch's membrane and/or alleviate ocular inflammation.

Symptom-Based Risk Factors for Retinal Tears and Detachments in Suspected Posterior Vitreous Detachment.

INTRODUCTION: The aim of this study was to determine symptom-level risk factors for retinal tear/retinal detachment (RT/RD) in our patients presenting with symptoms of posterior vitreous detachment (PVD). METHODS: We conducted a prospective cohort study of patients presenting to outpatient ophthalmology clinics at a single academic institution with complaint(s) of flashes, floaters, and/or subjective field loss (SFL). Patients received a standardized questionnaire regarding past ocular history and symptom characteristics including number, duration, and timing of flashes and floaters, prior to dilated ocular examination. Final diagnosis was categorized as RT/RD, PVD, ocular migraine, vitreous syneresis, or "other." Simple and multivariate logistic regressions were used to identify symptoms predictive of various pathologies. RESULTS: We recruited 237 patients (age 20-93 years) from March 2018 to March 2019. The most common diagnosis was PVD (141, 59.5%), followed by vitreous syneresis (38, 16.0%) and RT/RD (34, 14.3%). Of those with RT/RD, 16 (47.1%) had retinal tear and 15 (44.1%) had RD. Significant differences in demographic and examination-based factors were observed between these groups. Symptom-based predictive factors for RT/RD were the presence of subjective visual reduction (SVR; OR 2.77, p = 0.03) or SFL (OR 2.47, p = 0.04), and the absence of either floaters (OR 4.26, p = 0.04) or flashes (OR 2.95, p = 0.009). The number, duration, and timing of flashes and floaters did not predict the presence of RT/RD in our cohort. Within the RT/RD group, patients with RT were more likely to report floaters (100% vs. 66.7%, p = 0.018) and less likely to report SFL (0% vs. 86.7%, p < 0.001) compared to those with RD. CONCLUSION: While well-known demographic and exam-based risk factors for RT/RD exist in patients with PVD symptoms, the relative importance of symptom characteristics is less clear. We found that the presence of SVR and SFL, as well as the absence of either flashes or floaters, predicts RT/RD in patients with PVD symptoms. However, the number, duration, and timing of flashes and floaters may be less relevant in the triage of these patients.

Clarin-1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome.

Usher syndrome type 3 (USH3) is an autosomal recessively inherited disorder caused by mutations in the gene clarin-1 (CLRN1), leading to combined progressive hearing loss and retinal degeneration. The cellular distribution of CLRN1 in the retina remains uncertain, either because its expression levels are low or because its epitopes are masked. Indeed, in the adult mouse retina, Clrn1 mRNA is developmentally downregulated, detectable only by RT-PCR. In this study we used the highly sensitive RNAscope in situ hybridization assay and single-cell RNA-sequencing techniques to investigate the distribution of Clrn1 and CLRN1 in mouse and human retina, respectively. We found that Clrn1 transcripts in mouse tissue are localized to the inner retina during postnatal development and in adult stages. The pattern of Clrn1 mRNA cellular expression is similar in both mouse and human adult retina, with CLRN1 transcripts being localized in Müller glia, and not photoreceptors. We generated a novel knock-in mouse with a hemagglutinin (HA) epitope-tagged CLRN1 and showed that CLRN1 is expressed continuously at the protein level in the retina. Following enzymatic deglycosylation and immunoblotting analysis, we detected a single CLRN1-specific protein band in homogenates of mouse and human retina, consistent in size with the main CLRN1 isoform. Taken together, our results implicate Müller glia in USH3 pathology, placing this cell type to the center of future mechanistic and therapeutic studies to prevent vision loss in this disease. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The selective estrogen receptor modulator raloxifene mitigates the effect of all-trans-retinal toxicity in photoreceptor degeneration.

The retinoid cycle is a metabolic process in the vertebrate retina that continuously regenerates 11-cis-retinal (11-cisRAL) from the all-trans-retinal (atRAL) isomer. atRAL accumulation can cause photoreceptor degeneration and irreversible visual dysfunction associated with incurable blinding retinal diseases, such as Stargardt disease, retinitis pigmentosa (RP), and atrophic age-related macular degeneration (AMD). The underlying cellular mechanisms leading to retinal degeneration remain uncertain, although previous studies have shown that atRAL promotes calcium influx associated with cell apoptosis. To identify compounds that mitigate the effects of atRAL toxicity, here we developed an unbiased and robust image-based assay that can detect changes in intracellular calcium levels in U2OS cells. Using our assay in a high-throughput screen of 2,400 compounds, we noted that selective estrogen receptor modulators (SERMs) potently stabilize intracellular calcium and thereby counteract atRAL-induced toxicity. In a light-induced retinal degeneration mouse model (Abca4-/-Rdh8-/-), raloxifene (a benzothiophene-type scaffold SERM) prevented the onset of photoreceptor apoptosis and thus protected the retina from degeneration. The minor structural differences between raloxifene and one of its derivatives (Y 134) had a major impact on calcium homeostasis after atRAL exposure in vitro, and we verified this differential impact in vivo In summary, the SERM raloxifene has structural and functional neuroprotective effects in the retina. We propose that the highly sensitive image-based assay developed here could be applied for the discovery of additional drug candidates preventing photoreceptor degeneration.

Photic generation of 11-cis-retinal in bovine retinal pigment epithelium.

Photoisomerization of the 11-cis-retinal chromophore of rod and cone visual pigments to an all-trans-configuration is the initiating event for vision in vertebrates. The regeneration of 11-cis-retinal, necessary for sustained visual function, is an endergonic process normally conducted by specialized enzyme systems. However, 11-cis-retinal also can be formed through reverse photoisomerization from all-trans-retinal. A nonvisual opsin known as retinal pigment epithelium (RPE)-retinal G-protein-coupled receptor (RGR) was previously shown to mediate visual chromophore regeneration in photic conditions, but conflicting results have cast doubt on its role as a photoisomerase. Here, we describe high-level production of 11-cis-retinal from RPE membranes stimulated by illumination at a narrow band of wavelengths. This activity was associated with RGR and enhanced by cellular retinaldehyde-binding protein (CRALBP), which binds the 11-cis-retinal produced by RGR and prevents its re-isomerization to all-trans-retinal. The activity was recapitulated with cells heterologously expressing RGR and with purified recombinant RGR. Using an RGR variant, K255A, we confirmed that a Schiff base linkage at Lys-255 is critical for substrate binding and isomerization. Single-cell RNA-Seq analysis of the retina and RPE tissue confirmed that RGR is expressed in human and bovine RPE and Müller glia, whereas mouse RGR is expressed in RPE but not in Müller glia. These results provide key insights into the mechanisms of physiological retinoid photoisomerization and suggest a novel mechanism by which RGR, in concert with CRALBP, regenerates the visual chromophore in the RPE under sustained light conditions.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE.

The accumulation of lipids within drusen, the epidemiologic link of a high fat diet, and the identification of polymorphisms in genes involved in lipid metabolism that are associated with disease risk, have prompted interest in the role of lipid abnormalities in AMD. Despite intensive investigation, our understanding of how lipid abnormalities contribute to AMD development remains unclear. Lipid metabolism is tightly regulated, and its dysregulation can trigger excess lipid accumulation within the RPE and Bruch's membrane. The high oxidative stress environment of the macula can promote lipid oxidation, impairing their original function as well as producing oxidation-specific epitopes (OSE), which unless neutralized, can induce unwanted inflammation that additionally contributes to AMD progression. Considering the multiple layers of lipid metabolism and inflammation, and the ability to simultaneously target multiple pathways, microRNA (miRNAs) have emerged as important regulators of many age-related diseases including atherosclerosis and Alzheimer's disease. These diseases have similar etiologic characteristics such as lipid-rich deposits, oxidative stress, and inflammation with AMD, which suggests that miRNAs might influence lipid metabolism in AMD. In this review, we discuss the contribution of lipids to AMD pathobiology and introduce how miRNAs might affect lipid metabolism during lesion development. Establishing how miRNAs contribute to lipid accumulation in AMD will help to define the role of lipids in AMD, and open new treatment avenues for this enigmatic disease.

Melanoma subtypes demonstrate distinct PD-L1 expression profiles.

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

Lipids, oxidized lipids, oxidation-specific epitopes, and Age-related Macular Degeneration.

Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly in western societies. While antioxidant micronutrient treatment is available for intermediate non-neovascular disease, and effective anti-vascular endothelial growth factor treatment is available for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. The role of lipids, which accumulate in the macula, and their oxidation, has emerged as an important factor in disease development. These oxidized lipids can either directly contribute to tissue injury or react with amine on proteins to form oxidation-specific epitopes, which can induce an innate immune response. If inadequately neutralized, the inflammatory response from these epitopes can incite tissue injury during disease development. This review explores how the accumulation of lipids, their oxidation, and the ensuing inflammatory response might contribute to the pathogenesis of AMD. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder .

Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation.

The discovery that genetic abnormalities in complement factor H (FH) are associated with an increased risk for age-related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision-threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of the innate immunity system that plays a non-redundant role in controlling inflammation, regulates complement by interacting with complement components. Here, we show that PTX3 is induced by oxidative stress, a known cause of AMD, in the retinal pigmented epithelium (RPE). PTX3 deficiency in vitro and in vivo magnified complement activation induced by oxidative stress, leading to increased C3a, FB, and C3d, but not C5b-9 complex formation. Increased C3a levels, resulting from PTX3 deficiency, raised the levels of Il1b mRNA and secretion of activated interleukin (IL)-1ß by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation, resulting in enhanced IL-1ß, but not IL-18, production by the RPE. Thus, in the presence of PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL-1ß in sufficient abundance to, importantly, result in macrophages accumulating in the choroid. These results demonstrate that PTX3 acts as an essential brake for complement and inflammasome activation by regulating the abundance of FH in the RPE, and provide critical insights into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Complement factor H binds malondialdehyde epitopes and protects from oxidative stress.

Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.

Robotic Vitreoretinal Surgery.

PURPOSE: To review the current literature on robotic assistance for ophthalmic surgery, especially vitreoretinal procedures. METHODS: MEDLINE, Embase, and Web of Science databases were searched from inception to August, 2016, for articles relevant to the review topic. Queries included combinations of the terms: robotic eye surgery, ophthalmology, and vitreoretinal. RESULTS: In ophthalmology, proof-of-concept papers have shown the feasibility of performing many delicate anterior segment and vitreoretinal surgical procedures accurately with robotic assistance. Multiple surgical platforms have been designed and tested in animal eyes and phantom models. These platforms have the capability to measure forces generated and velocities of different surgical movements. "Smart" instruments have been designed to improve certain tasks such as membrane peeling and retinal vessel cannulations. CONCLUSION: Ophthalmic surgery, particularly vitreoretinal surgery, might have reached the limits of human physiologic performance. Robotic assistance can help overcome biologic limitations and improve our surgical performance. Clinical studies of robotic-assisted surgeries are needed to determine safety and feasibility of using this technology in patients.

STARGARDT DISEASE: Beyond Flecks and Atrophy.

PURPOSE: To identify changes in the outer retina in areas without atrophy or flecks of Stargardt disease (STGD) using spectral-domain optical coherence tomography. METHODS: Twenty-three STGD patients and 26 control subjects were assessed for outer retina (from the outer border of Bruch membrane [BrM] to the inner border of the inner segment ellipsoid zone [EZ]), BrM-retinal pigment epithelium apex, the EZ thickness, and apical process interdigitation zone. RESULTS: Patients with STGD had increased BrM-EZ thickness in areas without apparent disease versus control subjects at 1,000, 1,500, 2,000, and 2,500 µm superior and 1,500 µm, 2,000 µm, and 2,500 µm inferior to the fovea (P < 0.05 to P < 0.001), greatest difference (3.4 µm) at 2,500 µm superiorly. The BrM-retinal pigment epithelium segment showed larger fractional contribution of 0.48 to 0.51 to the overall BrM-EZ thickness compared with 0.35 to 0.42 in control subjects. The thickness of EZ and the interspace between the retinal pigment epithelium apex and EZ were smaller in the STGD patients (P < 0.05 to P < 0.001). Patients with STGD displayed an interrupted interdigitation zone in 16 (84.2%) of 19 eyes versus 6 (23.1%) of 26 eyes of the control subjects (P < 0.001). The BrM-EZ segment of the outer retina of STGD patients lacked the typical normal trilaminar pattern. CONCLUSION: Subtle changes are present within the BrM-EZ segment of the outer retina of STGD patients in areas that are devoid of atrophy and flecks. These findings suggest that pathologic changes in STGD are more widespread than that seen by clinical examination.

Rescuing Trafficking Mutants of the ATP-binding Cassette Protein, ABCA4, with Small Molecule Correctors as a Treatment for Stargardt Eye Disease.

Stargardt disease is the most common form of early onset macular degeneration. Mutations in ABCA4, a member of the ATP-binding cassette (ABC) family, are associated with Stargardt disease. Here, we have examined two disease-causing mutations in the NBD1 region of ABCA4, R1108C, and R1129C, which occur within regions of high similarity with CFTR, another ABC transporter gene, which is associated with cystic fibrosis. We show that R1108C and R1129C are both temperature-sensitive processing mutants that engage the cellular quality control mechanism and show a strong interaction with the chaperone Hsp 27. Both mutant proteins also interact with HDCAC6 and are degraded in the aggresome. We also demonstrate that novel corrector compounds that are being tested as treatment for cystic fibrosis, such as VX-809, can rescue the processing of the ABCA4 mutants, particularly their expression at the cell surface, and can reduce their binding to HDAC6. Thus, our data suggest that VX-809 can potentially be developed as a new therapy for Stargardt disease, for which there is currently no treatment.

Concise Review: Using Stem Cells to Prevent the Progression of Myopia-A Concept.

The prevalence of myopia has increased in modern society due to the educational load of children. This condition is growing rapidly, especially in Asian countries where it has already reached a pandemic level. Typically, the younger the child's age at the onset of myopia, the more rapidly the condition will progress and the greater the likelihood that it will develop the known sight-threatening complications of high myopia. This rise in incidence of severe myopia has contributed to an increased frequency of eye diseases in adulthood, which often complicate therapeutic procedures. Currently, no treatment is available to prevent myopia progression. Stem cell therapy can potentially address two components of myopia. Regardless of the exact etiology, myopia is always associated with scleral weakness. In this context, a strategy aimed at scleral reinforcement by transplanting connective tissue-supportive mesenchymal stem cells is an attractive approach that could yield effective and universal therapy. Sunlight exposure appears to have a protective effect against myopia. It is postulated that this effect is mediated via local ocular production of dopamine. With a variety of dopamine-producing cells already available for the treatment of Parkinson's disease, stem cells engineered for dopamine production could be used for the treatment of myopia. In this review, we further explore these concepts and present evidence from the literature to support the use of stem cell therapy for the treatment of myopia.

An easy, rapid method to isolate RPE cell protein from the mouse eye.

The retinal pigment epithelium (RPE) is essential for maintaining the health of the neural retina. RPE cell dysfunction plays a critical role in many common blinding diseases including age-related macular degeneration (AMD), diabetic retinopathy, retinal dystrophies. Mouse models of ocular disease are commonly used to study these blinding diseases. Since isolating the RPE from the choroid has been challenging, most techniques separate the RPE from the retina, but not the choroid. As a result, the protein signature actually represents a heterogeneous population of cells that may not accurately represent the RPE response. Herein, we describe a method for separating proteins from the RPE that is free from retinal and choroidal contamination. After removing the anterior segment and retina from enucleated mouse eyes, protein from the RPE was extracted separately from the choroid by incubating the posterior eyecup with a protein lysis buffer for 10 min. Western blot analysis identified RPE65, an RPE specific protein in the RPE lysates, but not in choroidal lysates. The RPE lysates were devoid of rhodopsin and collagen VI, which are abundant in the retina and choroid, respectively. This technique will be very helpful for measuring the protein signal from the RPE without retinal or choroidal contamination.

Lysosomes: Regulators of autophagy in the retinal pigmented epithelium.

The retinal pigmented epithelium (RPE) is critically important to retinal homeostasis, in part due to its very active processes of phagocytosis and autophagy. Both of these processes depend upon the normal functioning of lysosomes, organelles which must fuse with (auto)phagosomes to deliver the hydrolases that effect degradation of cargo. It has become clear that signaling through mTOR complex 1 (mTORC1), is very important in the regulation of lysosomal function. This signaling pathway is becoming a target for therapeutic intervention in diseases, including age-related macular degeneration (AMD), where lysosomal function is defective. In addition, our laboratory has been studying animal models in which the gene (Cryba1) for ßA3/A1-crystallin is deficient. These animals exhibit impaired lysosomal clearance in the RPE and pathological signs that are similar to some of those seen in AMD patients. The data demonstrate that ßA3/A1-crystallin localizes to lysosomes in the RPE and that it is a binding partner of V-ATPase, the proton pump that acidifies the lysosomal lumen. This suggests that ßA3/A1-crystallin may also be a potential target for therapeutic intervention in AMD. In this review, we focus on effector molecules that impact the lysosomal-autophagic pathway in RPE cells.

Biology of p62/sequestosome-1 in Age-Related Macular Degeneration (AMD).

p62/sequestosome-1 is a multidimensional protein that interacts with many signaling factors, and regulates a variety of cellular functions including inflammation, apoptosis, and autophagy. Our previous work has revealed in the retinal pigment epithelium (RPE) that p62 promotes autophagy and simultaneously enhances an Nrf2-mediated antioxidant response to protect against acute oxidative stress. Several recent studies demonstrated that p62 contributes to NFkB mediated inflammation and inflammasome activation under certain circumstances, raising the question of whether p62 protects against or contributes to tissue injury. Herein, we will review the general characteristics of p62, focusing on its pro- and anti-cell survival roles within different physiological/pathological contexts, and discuss the potential of p62 as a therapeutic target for AMD.