-
Progress in Retinal and Eye Research Jan 2020Quantitative fundus autofluorescence (qAF) is an approach that is built on a confocal scanning laser platform and used to measure the intensity of the inherent... (Review)
Review
Quantitative fundus autofluorescence (qAF) is an approach that is built on a confocal scanning laser platform and used to measure the intensity of the inherent autofluorescence of retina elicited by short-wavelength (488 nm) excitation. Being non-invasive, qAF does not interrupt tissue architecture, thus allowing for structural correlations. The spectral features, cellular origin and topographic distribution of the natural autofluorescence of the fundus indicate that it is emitted from retinaldehyde-adducts that form in photoreceptor cells and accumulate, under most conditions, in retinal pigment epithelial cells. The distributions and intensities of fundus autofluorescence deviate from normal in many retinal disorders and it is widely recognized that these changing patterns can aid in the diagnosis and monitoring of retinal disease. The standardized protocol employed by qAF involves the normalization of fundus grey levels to a fluorescent reference installed in the imaging instrument. Together with corrections for magnification and anterior media absorption, this approach facilitates comparisons with serial images and images acquired within groups of patients. Here we provide a comprehensive summary of the principles and practice of qAF and we highlight recent efforts to elucidate retinal disease processes by combining qAF with multi-modal imaging.
Topics: Fluorescein Angiography; Fundus Oculi; Humans; Macular Degeneration; Ophthalmoscopy; Retinal Pigment Epithelium; Tomography, Optical Coherence
PubMed: 31472235
DOI: 10.1016/j.preteyeres.2019.100774 -
The FEBS Journal Apr 2022Retinal inflammation underlies multiple prevalent ocular and neurological diseases. Similar inflammatory processes are observed in glaucomatous optic neuropathy,... (Review)
Review
Retinal inflammation underlies multiple prevalent ocular and neurological diseases. Similar inflammatory processes are observed in glaucomatous optic neuropathy, age-related macular degeneration, retinitis pigmentosa, posterior uveitis, Alzheimer's disease, and Parkinson's disease. In particular, human and animal studies have demonstrated the important role microglia/macrophages play in initiating and maintaining a pro-inflammatory environment in degenerative processes impacting vision. On the other hand, microglia have also been shown to have a protective role in multiple central nervous system diseases. Identifying the mechanisms underlying cell dysfunction and death is the first step toward developing novel therapeutics for these diseases impacting the central nervous system. In addition to reviewing recent key studies defining important mediators of retinal inflammation, with an emphasis on translational studies that bridge this research from bench to bedside, we also highlight a promising therapeutic class of medications, the glucagon-like peptide-1 receptor agonists. Finally, we propose areas where additional research is necessary to identify mechanisms that can be modulated to shift the balance from a neurotoxic to a neuroprotective retinal environment.
Topics: Animals; Brain; Inflammation; Microglia; Myeloid Cells; Neurodegenerative Diseases; Retina; Retinitis Pigmentosa
PubMed: 34478598
DOI: 10.1111/febs.16177 -
Biochemical Society Transactions Feb 2022Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conserved enzyme in purine metabolism that is tightly regulated on multiple levels. IMPDH has a critical role... (Review)
Review
Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conserved enzyme in purine metabolism that is tightly regulated on multiple levels. IMPDH has a critical role in purine biosynthesis, where it regulates flux at the branch point between adenine and guanine nucleotide synthesis, but it also has a role in transcription regulation and other moonlighting functions have been described. Vertebrates have two isoforms, IMPDH1 and IMPDH2, and point mutations in each are linked to human disease. Mutations in IMPDH2 in humans are associated with neurodevelopmental disease, but the effects of mutations at the enzyme level have not yet been characterized. Mutations in IMPDH1 lead to retinal degeneration in humans, and recent studies have characterized how they cause functional defects in regulation. IMPDH1 is expressed as two unique splice variants in the retina, a tissue with very high and specific demands for purine nucleotides. Recent studies have revealed functional differences among splice variants, demonstrating that retinal variants up-regulate guanine nucleotide synthesis by reducing sensitivity to feedback inhibition by downstream products. A better understanding of the role of IMPDH1 in the retina and the characterization of an animal disease model will be critical for determining the molecular mechanism of IMPDH1-associated blindness.
Topics: Animals; IMP Dehydrogenase; Mutation; Protein Isoforms; Retina; Retinal Degeneration
PubMed: 35191957
DOI: 10.1042/BST20210446 -
Biomolecules Feb 2023Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and... (Review)
Review
Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation.
Topics: Humans; Retinal Dystrophies; Retina; Retinal Cone Photoreceptor Cells; Mutation; Vision, Ocular
PubMed: 36830640
DOI: 10.3390/biom13020271 -
Cell Reports Sep 2023Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are...
Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.
Topics: Humans; Retinal Cone Photoreceptor Cells; Transcriptome; Reactive Oxygen Species; Retina; Retinitis Pigmentosa
PubMed: 37656622
DOI: 10.1016/j.celrep.2023.113054 -
Indian Journal of Ophthalmology Jul 2022Lactoferrin (LF) is an iron-binding glycoprotein released from mucous secreting cells and neutrophils. LF can be used in a broad range of eye diseases related to the... (Review)
Review
Lactoferrin (LF) is an iron-binding glycoprotein released from mucous secreting cells and neutrophils. LF can be used in a broad range of eye diseases related to the retina, cornea, and optic nerve. The retina is particularly affected by oxidative stress inside the photoreceptor being constantly exposed to light which induces accumulation of reactive oxygen species (ROS) in the retinal pigmented epithelium (RPE) causing damage to photoreceptor recycling. Retinitis pigmentosa (RP) and macular degeneration are inherited retinopathies that consist of different disease-causing genes, that cause mutations with highly varied clinical consequences. Age-related macular degeneration is a chronic disease of the retina and one of the major causes of sight loss. This review provides an application of lactoferrin and LF-based nano-formulations or nanoparticles in the field of retinal diseases or corneal diseases such as retinitis pigmentosa, retinoblastoma, age-related macular degeneration (AMD), keratoconus and uveitis. Several studies have found that lactoferrin's antibacterial activity is not limited to its iron sequestration, but also its ability as a nanoparticle that acts as a carrier to deliver drugs by crossing the blood-retina barrier (BRB) and its involvement in cell cycle control, which is not possible by many transferrin proteins.
Topics: Humans; Iron; Lactoferrin; Macular Degeneration; Retina; Retinitis Pigmentosa
PubMed: 35791114
DOI: 10.4103/ijo.IJO_303_22 -
Genes Feb 2023The epigenome represents a vast molecular apparatus that writes, reads, and erases chemical modifications to the DNA and histone code without changing the DNA base-pair... (Review)
Review
The epigenome represents a vast molecular apparatus that writes, reads, and erases chemical modifications to the DNA and histone code without changing the DNA base-pair sequence itself. Recent advances in molecular sequencing technology have revealed that epigenetic chromatin marks directly mediate critical events in retinal development, aging, and degeneration. Epigenetic signaling regulates retinal progenitor (RPC) cell cycle exit during retinal laminar development, giving rise to retinal ganglion cells (RGCs), amacrine cells, horizontal cells, bipolar cells, photoreceptors, and Müller glia. Age-related epigenetic changes such as DNA methylation in the retina and optic nerve are accelerated in pathogenic conditions such as glaucoma and macular degeneration, but reversing these epigenetic marks may represent a novel therapeutic target. Epigenetic writers also integrate environmental signals such as hypoxia, inflammation, and hyperglycemia in complex retinal conditions such as diabetic retinopathy (DR) and choroidal neovascularization (CNV). Histone deacetylase (HDAC) inhibitors protect against apoptosis and photoreceptor degeneration in animal models of retinitis pigmentosa (RP). The epigenome represents an intriguing therapeutic target for age-, genetic-, and neovascular-related retinal diseases, though more work is needed before advancement to clinical trials.
Topics: Animals; Retina; Retinal Degeneration; Macular Degeneration; Retinal Ganglion Cells; Epigenesis, Genetic
PubMed: 36833344
DOI: 10.3390/genes14020417 -
Methods in Enzymology 2022Carotenoids constitute an essential dietary component of animals and other non-carotenogenic species which use these pigments in both their modified and unmodified...
Carotenoids constitute an essential dietary component of animals and other non-carotenogenic species which use these pigments in both their modified and unmodified forms. Animals utilize uncleaved carotenoids to mitigate light damage and oxidative stress and to signal fitness and health. Carotenoids also serve as precursors of apocarotenoids including retinol, and its retinoid metabolites, which carry out essential functions in animals by forming the visual chromophore 11-cis-retinaldehyde. Retinoids, such as all-trans-retinoic acid, can also act as ligands of nuclear hormone receptors. The fact that enzymes and biochemical pathways responsible for the metabolism of carotenoids in animals bear resemblance to the ones in plants and other carotenogenic species suggests an evolutionary relationship. We will explore some of the modes of transmission of carotenoid genes from carotenogenic species to metazoans. This apparent relationship has been successfully exploited in the past to identify and characterize new carotenoid and retinoid modifying enzymes. We will review approaches used to identify putative animal carotenoid enzymes, and we will describe methods used to functionally validate and analyze the biochemistry of carotenoid modifying enzymes encoded by animals.
Topics: Animals; Carotenoids; Plants; Retinaldehyde; Retinoids
PubMed: 36008015
DOI: 10.1016/bs.mie.2022.05.005 -
Proceedings of the National Academy of... Jun 2023Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the...
Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11- retinal, were examined. Reducing chromophore supply via mutations in or resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of and , genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina.
Topics: Mice; Animals; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Color Vision; Disease Models, Animal
PubMed: 37252956
DOI: 10.1073/pnas.2217885120 -
Clinical & Experimental Optometry Jan 2021Optical coherence tomography angiography (OCT-A) is a non-invasive imaging modality for assessing the vasculature within ocular structures including the retina, macula,... (Review)
Review
Optical coherence tomography angiography (OCT-A) is a non-invasive imaging modality for assessing the vasculature within ocular structures including the retina, macula, choroid and optic nerve. OCT-A has a wide range of clinical applications in various optometric conditions which have been independently reported in the literature. This paper aims to present a review of the current literature on the clinical application of OCT-A in optometric practice as well as to analyse and evaluate the quality of the available evidence. This review included 78 articles from a literature search conducted on 26 May 2019 across the following databases: Cochrane Library of Systematic Reviews, Medline, Scopus and Web of Science. Primary ocular pathologies discussed in this review include glaucoma, diabetic retinopathy, age-related macular degeneration, myopia, acquired and congenital macular dystrophies, epiretinal membrane, retinal vein occlusion, retinitis pigmentosa, choroidal melanoma, uveitis, central serous chorioretinopathy, amblyopia and optic neuropathies. Primary outcome variables included vessel density, foveal avascular zone area and diameter, flow velocity and flow index. This review aims to evaluate the evidence available for OCT-A applications in diagnosis and prognosis of ocular conditions in an optometric setting.
Topics: Fluorescein Angiography; Humans; Macula Lutea; Retina; Retinal Vessels; Systematic Reviews as Topic; Tomography, Optical Coherence
PubMed: 32285493
DOI: 10.1111/cxo.13068