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Cellular and Molecular Neurobiology Apr 2023Retinitis pigmentosa (RP) is a group of genetic disorders resulting in inherited blindness due to the degeneration of rod and cone photoreceptors. The various mechanisms... (Review)
Review
Retinitis pigmentosa (RP) is a group of genetic disorders resulting in inherited blindness due to the degeneration of rod and cone photoreceptors. The various mechanisms underlying rod degeneration primarily rely on genetic mutations, leading to night blindness initially. Cones gradually degenerate after rods are almost eliminated, resulting in varying degrees of visual disability and blindness. The mechanism of cone degeneration remains unclear. An understanding of the mechanisms underlying cone degeneration in RP, a highly heterogeneous disease, is essential to develop novel treatments of RP. Herein, we review recent advancements in the five hypotheses of cone degeneration, including oxidative stress, trophic factors, metabolic stress, light damage, and inflammation activation. We also discuss the connection among these theories to provide a better understanding of secondary cone degeneration in RP. Five current mechanisms of cone degenerations in RP Interactions among different pathways are involved in RP.
Topics: Humans; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Blindness; Oxidative Stress
PubMed: 35792991
DOI: 10.1007/s10571-022-01243-2 -
Annual Review of Vision Science Sep 2020Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and... (Review)
Review
Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and cells of the retinal pigment epithelium (RPE), which provide essential metabolites, phagocytose waste, and control the composition of the surrounding microenvironment. A third vital supporting cell type, the retinal microglia, can provide photoreceptors with neurotrophic support or exacerbate neuroinflammation and hasten neuronal cell death. Understanding the physiological requirements for photoreceptor homeostasis and the factors that drive microglia to best promote photoreceptor survival has important implications for the treatment and prevention of blinding degenerative diseases like retinitis pigmentosa and age-related macular degeneration.
Topics: Animals; Apoptosis; Ependymoglial Cells; Humans; Macrophage Activation; Phagocytosis; Photoreceptor Cells; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Pigment Epithelium; Signal Transduction
PubMed: 32936734
DOI: 10.1146/annurev-vision-121219-081730 -
Biochemical Pharmacology Sep 2022Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and... (Review)
Review
Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.
Topics: Carnitine; Humans; Infant, Newborn; Mitochondria; Photoreceptor Cells; Retina; Retinal Degeneration
PubMed: 35835206
DOI: 10.1016/j.bcp.2022.115168 -
Absence of CEP78 causes photoreceptor and sperm flagella impairments in mice and a human individual.ELife Feb 2023Cone-rod dystrophy (CRD) is a genetically inherited retinal disease that can be associated with male infertility, while the specific genetic mechanisms are not well...
Cone-rod dystrophy (CRD) is a genetically inherited retinal disease that can be associated with male infertility, while the specific genetic mechanisms are not well known. Here, we report as a causative gene of a particular syndrome including CRD and male infertility with multiple morphological abnormalities of sperm flagella (MMAF) both in human and mouse. knockout mice exhibited impaired function and morphology of photoreceptors, typified by reduced ERG amplitudes, disrupted translocation of cone arrestin, attenuated and disorganized photoreceptor outer segments (OS) disks and widen OS bases, as well as interrupted connecting cilia elongation and abnormal structures. deletion also caused male infertility and MMAF, with disordered '9+2' structure and triplet microtubules in sperm flagella. Intraflagellar transport (IFT) proteins IFT20 and TTC21A are identified as interacting proteins of CEP78. Furthermore, CEP78 regulated the interaction, stability, and centriolar localization of its interacting protein. Insufficiency of CEP78 or its interacting protein causes abnormal centriole elongation and cilia shortening. Absence of CEP78 protein in human caused similar phenotypes in vision and MMAF as mice. Collectively, our study supports the important roles of defects in centriole and ciliary dysfunctions and molecular pathogenesis of such multi-system syndrome.
Topics: Humans; Male; Animals; Mice; Semen; Sperm Tail; Proteins; Photoreceptor Cells; Infertility, Male; Flagella; Cell Cycle Proteins
PubMed: 36756949
DOI: 10.7554/eLife.76157 -
Pflugers Archiv : European Journal of... Sep 2021Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary intracellular messenger for the visual signaling pathway that converts a light stimulus... (Review)
Review
Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary intracellular messenger for the visual signaling pathway that converts a light stimulus into an electrical response. cGMP metabolism in the signal-transducing photoreceptor outer segment reflects the balance of cGMP synthesis (catalyzed by guanylyl cyclase) and degradation (catalyzed by the photoreceptor phosphodiesterase, PDE6). Upon light stimulation, rapid activation of PDE6 by the heterotrimeric G-protein (transducin) triggers a dramatic drop in cGMP levels that lead to cell hyperpolarization. Following cessation of the light stimulus, the lifetime of activated PDE6 is also precisely regulated by additional processes. This review summarizes recent advances in the structural characterization of the rod and cone PDE6 catalytic and regulatory subunits in the context of previous biochemical studies of the enzymological properties and allosteric regulation of PDE6. Emphasis is given to recent advances in understanding the structural and conformational changes underlying the mechanism by which the activated transducin α-subunit binds to-and relieves inhibition of-PDE6 catalysis that is controlled by its intrinsically disordered, inhibitory γ-subunit. The role of the regulator of G-protein signaling 9-1 (RGS9-1) in regulating the lifetime of the transducin-PDE6 is also briefly covered. The therapeutic potential of pharmacological compounds acting as inhibitors or activators targeting PDE6 is discussed in the context of inherited retinal diseases resulting from mutations in rod and cone PDE6 genes as well as other inherited defects that arise from excessive cGMP accumulation in retinal photoreceptor cells.
Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 6; Humans; Protein Structure, Secondary; Protein Structure, Tertiary; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 33860373
DOI: 10.1007/s00424-021-02562-x -
Eye (London, England) Aug 2023The importance of the visual system to birds for behaviours from feeding, mate choice, flying, navigation and determination of seasons, together with the presence of... (Review)
Review
The importance of the visual system to birds for behaviours from feeding, mate choice, flying, navigation and determination of seasons, together with the presence of photoreceptors in the retina, the pineal and the brain, render the avian visual system a particularly fruitful model for understanding of eye-brain interactions. In this review we will particularly focus on the pigeon, since here we have a brain stereotactically mapped and a genome fully sequenced, together with a particular bird, the homing pigeon, with remarkable ability to navigate over hundreds of miles and return to exactly the same roosting site with exceptional precision. We might denigrate the avian species by the term bird brained, but here are animals with phenomenal abilities to use their exceptional vision, their eagle eyedness, to best advantage.
Topics: Animals; Birds; Brain; Retina; Vision, Ocular; Photoreceptor Cells
PubMed: 37353509
DOI: 10.1038/s41433-023-02568-y -
Science Signaling Jul 2023Precise synapse formation is essential for normal functioning of the nervous system. Retinal photoreceptors establish selective contacts with bipolar cells, aligning the...
Precise synapse formation is essential for normal functioning of the nervous system. Retinal photoreceptors establish selective contacts with bipolar cells, aligning the neurotransmitter release apparatus with postsynaptic signaling cascades. This involves transsynaptic assembly between the dystroglycan-dystrophin complex on the photoreceptor and the orphan receptor GPR179 on the bipolar cell, which is mediated by the extracellular matrix protein pikachurin (also known as EGFLAM). This complex plays a critical role in the synaptic organization of photoreceptors and signal transmission, and mutations affecting its components cause blinding disorders in humans. Here, we investigated the structural organization and molecular mechanisms by which pikachurin orchestrates transsynaptic assembly and solved structures of the human pikachurin domains by x-ray crystallography and of the GPR179-pikachurin complex by single-particle, cryo-electron microscopy. The structures reveal molecular recognition principles of pikachurin by the Cache domains of GPR179 and show how the interaction is involved in the transsynaptic alignment of the signaling machinery. Together, these data provide a structural basis for understanding the synaptic organization of photoreceptors and ocular pathology.
Topics: Humans; Carrier Proteins; Cryoelectron Microscopy; Extracellular Matrix Proteins; Photoreceptor Cells; Synapses
PubMed: 37490546
DOI: 10.1126/scisignal.add9539 -
Cell Death & Disease Dec 2023Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events...
Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events has not been well delineated, primarily because of an inadequate understanding of the immunological processes involved in photoreceptor degeneration, especially that of peripheral leukocytes that infiltrate the subretinal space and retinal tissues. In this work, we characterized the role of leukocyte infiltration within the detached retina. We observed that CD45 CD11b Ly6G neutrophils and CD45 CD11b Ly6G Ly6C monocytes are the predominant peripheral immune cell populations that infiltrate the retinal and subretinal space after detachment. Selective depletion of monocytes or neutrophils using cell-specific targeting is neuroprotective for photoreceptors. These results indicate that peripheral innate immune cells contribute to photoreceptor degeneration, and targeting these immune cell populations could be therapeutic during retinal detachment.
Topics: Humans; Animals; Retinal Detachment; Monocytes; Neutrophils; Photoreceptor Cells; Retina; Retinal Degeneration; Photoreceptor Cells, Vertebrate; Disease Models, Animal
PubMed: 38102109
DOI: 10.1038/s41419-023-06350-6 -
Progress in Retinal and Eye Research Sep 2019In this review, we summarize studies investigating the types and distribution of voltage- and calcium-gated ion channels in the different classes of retinal neurons:... (Review)
Review
In this review, we summarize studies investigating the types and distribution of voltage- and calcium-gated ion channels in the different classes of retinal neurons: rods, cones, horizontal cells, bipolar cells, amacrine cells, interplexiform cells, and ganglion cells. We discuss differences among cell subtypes within these major cell classes, as well as differences among species, and consider how different ion channels shape the responses of different neurons. For example, even though second-order bipolar and horizontal cells do not typically generate fast sodium-dependent action potentials, many of these cells nevertheless possess fast sodium currents that can enhance their kinetic response capabilities. Ca channel activity can also shape response kinetics as well as regulating synaptic release. The L-type Ca channel subtype, Ca1.4, expressed in photoreceptor cells exhibits specific properties matching the particular needs of these cells such as limited inactivation which allows sustained channel activity and maintained synaptic release in darkness. The particular properties of K and Cl channels in different retinal neurons shape resting membrane potentials, response kinetics and spiking behavior. A remaining challenge is to characterize the specific distributions of ion channels in the more than 100 individual cell types that have been identified in the retina and to describe how these particular ion channels sculpt neuronal responses to assist in the processing of visual information by the retina.
Topics: Amacrine Cells; Animals; Humans; Ion Channels; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Retinal Neurons; Retinal Rod Photoreceptor Cells; Synaptic Transmission
PubMed: 31078724
DOI: 10.1016/j.preteyeres.2019.05.001 -
Drug Discovery Today Aug 2019The photoreceptors of the retina are afflicted by diseases that still often lack satisfactory treatment options. Although suitable drugs might be available in some... (Review)
Review
The photoreceptors of the retina are afflicted by diseases that still often lack satisfactory treatment options. Although suitable drugs might be available in some cases, the delivery of these compounds into the eye and across the blood-retinal barrier remains a significant challenge for therapy development. Here, we review the routes of drug administration to the retina and highlight different options for drug delivery to the photoreceptor cells.
Topics: Animals; Drug Delivery Systems; Humans; Pharmaceutical Preparations; Photoreceptor Cells, Vertebrate; Retina
PubMed: 30877076
DOI: 10.1016/j.drudis.2019.03.004