Functional microRNA targetome undergoes degeneration-induced shift in the retina

Abstract Background MicroRNA (miRNA) play a significant role in the pathogenesis of complex neurodegenerative diseases including age-related macular degeneration (AMD), acting as post-transcriptional gene suppressors through their association with argonaute 2 (AGO2) - a key member of the RNA Induced Silencing Complex (RISC). Identifying the retinal miRNA/mRNA interactions in health and disease will provide important insight into the key pathways miRNA regulate in disease pathogenesis and may lead to potential therapeutic targets to mediate retinal degeneration. Methods To identify the active miRnome targetome interactions in the healthy and degenerating retina, AGO2 HITS-CLIP was performed using a rodent model of photoreceptor degeneration. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data was performed to identify the cellular location of AGO2 and key members of the microRNA targetome in the retina. AGO2 findings were verified by in situ hybridization (RNA) and immunohistochemistry (protein). Results Analysis revealed a similar miRnome between healthy and damaged retinas, however, a shift in the active targetome was observed with an enrichment of miRNA involvement in inflammatory pathways. This shift was further demonstrated by a change in the seed binding regions of miR-124-3p, the most abundant retinal AGO2-bound miRNA, and has known roles in regulating retinal inflammation. Additionally, photoreceptor cluster miR-183/96/182 were all among the most highly abundant miRNA bound to AGO2. Following damage, AGO2 expression was localized to the inner retinal layers and more in the OLM than in healthy retinas, indicating a locational miRNA response to retinal damage. Conclusions This study provides important insight into the alteration of miRNA regulatory activity that occurs as a response to retinal degeneration and explores the miRNA-mRNA targetome as a consequence of retinal degenerations. Further characterisation of these miRNA/mRNA interactions in the context of the degenerating retina may provide an important insight into the active role these miRNA may play in diseases such as AMD.

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Functional microRNA targetome undergoes degeneration-induced shift in the retina

10.1101/2020.05.27.118307 ◽

2020 ◽

Author(s):

Joshua A. Chu-Tan ◽

Zhi-Ping Feng ◽

Yvette Wooff ◽

Adrian V. Cioanca ◽

Ulrike Schumann ◽

...

Keyword(s):

Mouse Model ◽

Neurodegenerative Diseases ◽

Macular Degeneration ◽

Retinal Degeneration ◽

Significant Role ◽

Age Related Macular Degeneration ◽

Retinal Damage ◽

Regulatory Activity ◽

Age Related ◽

Insight Into

SummaryMicroRNA (miRNA) play a significant role in the pathogenesis of complex neurodegenerative diseases, including age-related macular degeneration, acting as post-transcriptional gene suppressors through their association with argonaute (AGO) protein family members. However, to understand their role in disease, investigation into the regulatory nature of miRNA with their targets is required. To identify the active-miRnome-targetome interactions in the degenerating retina, AGO2 HITS-CLIP was performed using a mouse model of retinal degeneration. Analysis revealed a similar miRnome between healthy and damaged retinas, however, a shift in the active targetome was observed. This shift was also demonstrated by a change in the seed binding regions of miR-124-3p, the most abundant retinal miRNA loaded in AGO2. Following damage, AGO2 was localised to the inner retinal layers indicating a locational miRNA response to retinal damage. This study provides important insight into the alteration of miRNA regulatory activity that occurs as a response to retinal degeneration.

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Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

Life ◽

10.3390/life11070635 ◽

2021 ◽

Vol 11 (7) ◽

pp. 635

Author(s):

Monica L. Hu ◽

Joel Quinn ◽

Kanmin Xue

Keyword(s):

Risk Factor ◽

Apolipoprotein E ◽

Macular Degeneration ◽

Amyloid Beta ◽

Complement System ◽

Genetic Risk ◽

Age Related Macular Degeneration ◽

Age Related ◽

Retinal Inflammation ◽

The Complement System

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer's disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

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Bone Morphogenetic Proteins and Diabetic Retinopathy

Biomolecules ◽

10.3390/biom11040593 ◽

2021 ◽

Vol 11 (4) ◽

pp. 593

Author(s):

Khaled Elmasry ◽

Samar Habib ◽

Mohamed Moustafa ◽

Mohamed Al-Shabrawey

Keyword(s):

Diabetic Retinopathy ◽

Bone Morphogenetic Proteins ◽

Potential Role ◽

Microvascular Dysfunction ◽

Cardiovascular Complications ◽

Bmp Signaling ◽

Age Related Macular Degeneration ◽

Age Related ◽

Retinal Inflammation ◽

Underlying Mechanisms

Bone morphogenetic proteins (BMPs) play an important role in bone formation and repair. Recent studies underscored their essential role in the normal development of several organs and vascular homeostasis in health and diseases. Elevated levels of BMPs have been linked to the development of cardiovascular complications of diabetes mellitus. However, their particular role in the pathogenesis of microvascular dysfunction associated with diabetic retinopathy (DR) is still under-investigated. Accumulated evidence from our and others’ studies suggests the involvement of BMP signaling in retinal inflammation, hyperpermeability and pathological neovascularization in DR and age-related macular degeneration (AMD). Therefore, targeting BMP signaling in diabetes is proposed as a potential therapeutic strategy to halt the development of microvascular dysfunction in retinal diseases, particularly in DR. The goal of this review article is to discuss the biological functions of BMPs, their underlying mechanisms and their potential role in the pathogenesis of DR in particular.

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Potential Treatment of Retinal Diseases with Iron Chelators

Pharmaceuticals ◽

10.3390/ph11040112 ◽

2018 ◽

Vol 11 (4) ◽

pp. 112 ◽

Cited By ~ 13

Author(s):

Wanting Shu ◽

Joshua Dunaief

Keyword(s):

Retinal Degeneration ◽

Therapeutic Potential ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Body ◽

Age Related Macular Degeneration ◽

Hereditary Diseases ◽

Iron Chelators ◽

Excess Iron ◽

Age Related

Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation.

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Different Populations of Circulating Endothelial Cells in Patients with Age-Related Macular Degeneration: A Novel Insight into Pathogenesis

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.10-5756 ◽

2011 ◽

Vol 52 (1) ◽

pp. 93 ◽

Cited By ~ 22

Author(s):

Anna Machalinska ◽

Krzysztof Safranow ◽

Violetta Dziedziejko ◽

Katarzyna Mozolewska-Piotrowska ◽

Edyta Paczkowska ◽

...

Keyword(s):

Endothelial Cells ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Circulating Endothelial Cells ◽

Age Related ◽

Different Populations ◽

Insight Into

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Retinal Prosthesis in the Treatment of Retinitis Pigmentosa

Güncel Retina Dergisi (Current Retina Journal) ◽

10.37783/crj-0252 ◽

2021 ◽

pp. 140-149

Keyword(s):

Retinitis Pigmentosa ◽

Retinal Prosthesis ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Cone Dystrophy ◽

Research Groups ◽

Retinal Prostheses ◽

Retinal Degenerations ◽

Age Related ◽

Macular Diseases

Retinal prostheses are devices that receive an environmental visual stimulus, process it, and stimulate the degenerated retinal areas in order to produce a functionally efficient visual perception. Indications for implantation of these devices include hereditary retinal degenerations like retinitis pigmentosa, choroideremia, rod-cone dystrophy, and acquired macular diseases like geographic atrophy or fibrosis due to age-related macular degeneration. Clinically applied retinal prosthesis approaches can be classified as; epiretinal, subretinal, suprachoroidal, and scleral (transscleral suprachoroidal). In this paper, approaches of retinal prosthesis research groups, results of clinical trials, and the latest advances in their projects will be provided.

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Mechanisms and Treatment of Light-Induced Retinal Degeneration-Associated Inflammation: Insights from Biochemical Profiling of the Aqueous Humor

International Journal of Molecular Sciences ◽

10.3390/ijms21030704 ◽

2020 ◽

Vol 21 (3) ◽

pp. 704 ◽

Cited By ~ 3

Author(s):

Dmitry V. Chistyakov ◽

Viktoriia E. Baksheeva ◽

Veronika V. Tiulina ◽

Sergei V. Goriainov ◽

Nadezhda V. Azbukina ◽

...

Keyword(s):

Oxidative Stress ◽

Retinal Degeneration ◽

Aqueous Humor ◽

Rabbit Model ◽

Age Related Macular Degeneration ◽

Protective Effects ◽

Cyclooxygenase Inhibitor ◽

Degenerative Diseases ◽

Age Related ◽

Retinal Degenerative Diseases

Ocular inflammation contributes to the pathogenesis of blind-causing retinal degenerative diseases, such as age-related macular degeneration (AMD) or photic maculopathy. Here, we report on inflammatory mechanisms that are associated with retinal degeneration induced by bright visible light, which were revealed while using a rabbit model. Histologically and electrophysiologically noticeable degeneration of the retina is preceded and accompanied by oxidative stress and inflammation, as evidenced by granulocyte infiltration and edema in this tissue, as well as the upregulation of total protein, pro-inflammatory cytokines, and oxidative stress markers in aqueous humor (AH). Consistently, quantitative lipidomic studies of AH elucidated increase in the concentration of arachidonic (AA) and docosahexaenoic (DHA) acids and lyso-platelet activating factor (lyso-PAF), together with pronounced oxidative and inflammatory alterations in content of lipid mediators oxylipins. These alterations include long-term elevation of prostaglandins, which are synthesized from AA via cyclooxygenase-dependent pathways, as well as a short burst of linoleic acid derivatives that can be produced by both enzymatic and non-enzymatic free radical-dependent mechanisms. The upregulation of all oxylipins is inhibited by the premedication of the eyes while using mitochondria-targeted antioxidant SkQ1, whereas the accumulation of prostaglandins and lyso-PAF can be specifically suppressed by topical treatment with cyclooxygenase inhibitor Nepafenac. Interestingly, the most prominent antioxidant and anti-inflammatory benefits and overall retinal protective effects are achieved by simultaneous administrating of both drugs indicating their synergistic action. Taken together, these findings provide a rationale for using a combination of mitochondria-targeted antioxidant and cyclooxygenase inhibitor for the treatment of inflammatory components of retinal degenerative diseases.

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Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration

eLife ◽

10.7554/elife.45100 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 11

Author(s):

Federica Storti ◽

Katrin Klee ◽

Vyara Todorova ◽

Regula Steiner ◽

Alaa Othman ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Progressive Disease ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Central Vision ◽

Atp Binding Cassette Transporter ◽

Lipid Efflux ◽

Age Related ◽

Retinal Inflammation

Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 (ABCA1), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the ABCA1 AMD risk-conferring allele decreases ABCA1 expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.

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Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2015.0376 ◽

2016 ◽

Vol 374 (2079) ◽

pp. 20150376 ◽

Cited By ~ 7

Author(s):

Junhua Wang ◽

Peter D. Westenskow ◽

Mingliang Fang ◽

Martin Friedlander ◽

Gary Siuzdak

Keyword(s):

Stem Cell ◽

Retinal Pigment Epithelium ◽

Retinal Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Photoreceptor Degeneration ◽

Quantitative Metabolomics ◽

Fatty Acid Amides ◽

Age Related

Photoreceptor degeneration is characteristic of vision-threatening diseases including age-related macular degeneration. Photoreceptors are metabolically demanding cells in the retina, but specific details about their metabolic behaviours are unresolved. The quantitative metabolomics of retinal degeneration could provide valuable insights and inform future therapies. Here, we determined the metabolomic ‘fingerprint’ of healthy and dystrophic retinas in rat models using optimized metabolite extraction techniques. A number of classes of metabolites were consistently dysregulated during degeneration: vitamin A analogues, fatty acid amides, long-chain polyunsaturated fatty acids, acyl carnitines and several phospholipid species. For the first time, a distinct temporal trend of several important metabolites including DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid), all- trans -retinal and its toxic end-product N -retinyl- N -retinylidene-ethanolamine were observed between healthy and dystrophic retinas. In this study, metabolomics was further used to determine the temporal effects of the therapeutic intervention of grafting stem cell-derived retinal pigment epithelium (RPE) in dystrophic retinas, which significantly prevented photoreceptor atrophy in our previous studies. The result revealed that lipid levels such as phosphatidylethanolamine in eyes were restored in those animals receiving the RPE grafts. In conclusion, this study provides insight into the metabolomics of retinal degeneration, and further understanding of the efficacy of RPE transplantation. This article is part of the themed issue ‘Quantitative mass spectrometry’.

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Potential Sources and Roles of Adaptive Immunity in Age-Related Macular Degeneration: Shall We Rename AMD into Autoimmune Macular Disease?

Autoimmune Diseases ◽

10.1155/2014/532487 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Serge Camelo

Keyword(s):

T Cells ◽

Macular Degeneration ◽

Retinal Degeneration ◽

Adaptive Immunity ◽

Choroidal Neovascularization ◽

Vision Loss ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Age Related ◽

Pathologic Features

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly throughout the industrialized world. Its most prominent pathologic features are lesions involving the retinal pigment epithelium (RPE) the Bruch’s membrane, the degeneration of photoreceptors, and, in the most aggressive cases, choroidal neovascularization. Genetic associations between the risk of developing AMD and polymorphism within components of the complement system, as well as chemokine receptors expressed on microglial cells and macrophages, have linked retinal degeneration and choroidal neovascularization to innate immunity (inflammation). In addition to inflammation, players of the adaptive immunity including cytokines, chemokines, antibodies, and T cells have been detected in animal models of AMD and in patients suffering from this pathology. These observations suggest that adaptive immunity might play a role in different processes associated with AMD such as RPE atrophy, neovascularization, and retinal degeneration. To this date however, the exact roles (if any) of autoantibodies and T cells in AMD remain unknown. In this review we discuss the potential effects of adaptive immune responses in AMD pathogenesis.

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