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International Journal of Molecular... Apr 2021Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their... (Review)
Review
Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their axons and leads to visual loss and blindness. Risk factors for the onset and progression of glaucoma include systemic and ocular factors such as older age, lower ocular perfusion pressure, and intraocular pressure (IOP). Early signs of RGC damage comprise impairment of axonal transport, downregulation of specific genes and metabolic changes. The brain is often cited to be the highest energy-demanding tissue of the human body. The retina is estimated to have equally high demands. RGCs are particularly active in metabolism and vulnerable to energy insufficiency. Understanding the energy metabolism of the inner retina, especially of the RGCs, is pivotal for understanding glaucoma's pathophysiology. Here we review the key contributors to the high energy demands in the retina and the distinguishing features of energy metabolism of the inner retina. The major features of glaucoma include progressive cell death of retinal ganglions and optic nerve damage. Therefore, this review focuses on the energetic budget of the retinal ganglion cells, optic nerve and the relevant cells that surround them.
Topics: Animals; Energy Metabolism; Glaucoma; Humans; Retinal Ganglion Cells
PubMed: 33916246
DOI: 10.3390/ijms22073689 -
Development (Cambridge, England) Dec 2020Retinal ganglion cells (RGCs) serve as a crucial communication channel from the retina to the brain. In the adult, these cells receive input from defined sets of... (Review)
Review
Retinal ganglion cells (RGCs) serve as a crucial communication channel from the retina to the brain. In the adult, these cells receive input from defined sets of presynaptic partners and communicate with postsynaptic brain regions to convey features of the visual scene. However, in the developing visual system, RGC interactions extend beyond their synaptic partners such that they guide development before the onset of vision. In this Review, we summarize our current understanding of how interactions between RGCs and their environment influence cellular targeting, migration and circuit maturation during visual system development. We describe the roles of RGC subclasses in shaping unique developmental responses within the retina and at central targets. Finally, we highlight the utility of RNA sequencing and genetic tools in uncovering RGC type-specific roles during the development of the visual system.
Topics: Animals; Base Sequence; Brain; Cell Differentiation; Cell Movement; Humans; Retina; Retinal Ganglion Cells; Vision, Ocular
PubMed: 33288502
DOI: 10.1242/dev.196535 -
BioMed Research International 2023Glaucoma causes the degeneration of the retinal ganglion cells (RGCs) and their axons, inducing a tissue reshaping that affects both the retina and the optic nerve head.... (Review)
Review
Glaucoma causes the degeneration of the retinal ganglion cells (RGCs) and their axons, inducing a tissue reshaping that affects both the retina and the optic nerve head. Glaucoma care especially focuses on reducing intraocular pressure, a significant risk factor for progressive damage to the optic nerve. The use of natural treatments, such as herbs, vitamins, and minerals, is becoming increasingly popular today. While plants are a rich source of novel biologically active compounds, only a small percentage of them have been phytochemically examined and evaluated for their medicinal potential. It is necessary for eye care professionals to inform their glaucoma patients about the therapy, protection, and efficacy of commonly used herbal medicines, considering the widespread use of herbal medicines. The purpose of this review is to examine evidence related to the most widely used herbal medicines for the management and treatment of glaucoma, to better understand the potential benefits of these natural compounds as supplementary therapy.
Topics: Animals; Humans; Glaucoma; Retina; Retinal Ganglion Cells; Intraocular Pressure; Axons; Disease Models, Animal; Plant Extracts
PubMed: 38027044
DOI: 10.1155/2023/3105251 -
Biomolecules Jul 2021Glaucoma is a group of irreversible blinding eye diseases characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Currently, there is no... (Review)
Review
Glaucoma is a group of irreversible blinding eye diseases characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Currently, there is no effective method to fundamentally resolve the issue of RGC degeneration. Recent advances have revealed that visual function recovery could be achieved with stem cell-based therapy by replacing damaged RGCs with cell transplantation, providing nutritional factors for damaged RGCs, and supplying healthy mitochondria and other cellular components to exert neuroprotective effects and mediate transdifferentiation of autologous retinal stem cells to accomplish endogenous regeneration of RGC. This article reviews the recent research progress in the above-mentioned fields, including the breakthroughs in the fields of in vivo transdifferentiation of retinal endogenous stem cells and reversal of the RGC aging phenotype, and discusses the obstacles in the clinical translation of the stem cell therapy.
Topics: Animals; Glaucoma; Humans; Regeneration; Retinal Ganglion Cells; Stem Cell Transplantation; Stem Cells
PubMed: 34356611
DOI: 10.3390/biom11070987 -
Cells Jun 2023p58 is a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2α kinases involved in a wide range of cellular processes including protein synthesis,...
p58 is a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2α kinases involved in a wide range of cellular processes including protein synthesis, ER stress response, and macrophage-mediated inflammation. Systemic deletion of p58 leads to age-related loss of retinal ganglion cells (RGC) and exacerbates RGC damage induced by ischemia/reperfusion and increased intraocular pressure (IOP), suggesting a protective role of p58 in the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58 using conditional knockout (cKO) mouse lines where p58 is deleted in retinal neurons (Chx10-p58 cKO) or in myeloid cells (Lyz2-p58 cKO). In addition, we overexpressed p58 by adeno-associated virus (AAV) in the retina to examine the effect of p58 on RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58 by AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58 on reducing RGC injury. Conditional knockout of p58 in retinal neurons or in myeloid cells did not alter retinal structure or cellular composition. However, a significant reduction in the b wave of light-adapted electroretinogram (ERG) was observed in Chx10-p58 cKO mice. Deletion of p58 in retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58 in myeloid cells increased the microglia/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58 in macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58 is mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58 specifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.
Topics: Animals; Mice; Glaucoma; HSP40 Heat-Shock Proteins; Macrophage Activation; Macrophages; Microglia; Ocular Hypertension; Retinal Ganglion Cells
PubMed: 37371028
DOI: 10.3390/cells12121558 -
Cell Reports Jul 2022Classification and characterization of neuronal types are critical for understanding their function and dysfunction. Neuronal classification schemes typically rely on...
Classification and characterization of neuronal types are critical for understanding their function and dysfunction. Neuronal classification schemes typically rely on measurements of electrophysiological, morphological, and molecular features, but aligning such datasets has been challenging. Here, we present a unified classification of mouse retinal ganglion cells (RGCs), the sole retinal output neurons. We use visually evoked responses to classify 1,859 mouse RGCs into 42 types. We also obtain morphological or transcriptomic data from subsets and use these measurements to align the functional classification to publicly available morphological and transcriptomic datasets. We create an online database that allows users to browse or download the data and to classify RGCs from their light responses using a machine learning algorithm. This work provides a resource for studies of RGCs, their upstream circuits in the retina, and their projections in the brain, and establishes a framework for future efforts in neuronal classification and open data distribution.
Topics: Animals; Gene Expression; Mice; Retina; Retinal Ganglion Cells
PubMed: 35830791
DOI: 10.1016/j.celrep.2022.111040 -
Experimental Eye Research Jan 2023Retinal explant cultures provide a valuable system to study retinal function in vitro. This study established a new retinal explant culture method to prolong the...
Retinal explant cultures provide a valuable system to study retinal function in vitro. This study established a new retinal explant culture method to prolong the survival of retinal ganglion cells (RGCs). Explants were prepared in two different ways: with or without optic nerve. Retinas from newborn mice that had received an injection of MitoTracker Red into the contralateral superior colliculus to label axonal mitochondria were cultured as organotypic culture for 7 days in vitro. At several time points during the culture, viability of RGCs was assessed by multi-electrode array recording, and morphology by immunohistochemical methods. During the culture, the thickness of the retinal tissue in both groups gradually decreased, however, the structure of the layers of the retina could be identified. Massive apoptosis in the retinal ganglion cell layer (GCL) appeared on the first day of culture, thereafter the number of apoptotic cells decreased. Glial activation was observed throughout the culture, and there was no difference in morphology between the two groups. RGCs loss was exacerbated on 3day of culture, and RGCs loss in retinal explants with preserved optic nerve was significantly lower than in retinas that did not preserve the optic nerve. More and longer-lasting mitochondrial signals were observed in the injured area of the optic nerve-preserving explants. Retinal explants provide an invaluable tool for studying retinal function and developing treatments for ocular diseases. The optic nerve-preserving culture helps preserve the integrity of RGCs. The higher number of mitochondria in the nerve-preserving cultures may help maintain viability of RGCs.
Topics: Mice; Animals; Retinal Ganglion Cells; Retina; Axons; Optic Nerve; Mitochondria; Optic Nerve Injuries
PubMed: 36403849
DOI: 10.1016/j.exer.2022.109311 -
Molecular Therapy : the Journal of the... Jul 2023Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma....
Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS) and NS overexpression (NS) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS glaucomatous mice and increased pNFH expression. NS mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (MR-NS) resistant to oxidative deactivation. Intravitreal administration of MR-NS was observed to rescue the RGC degenerative phenotype in NS mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma.
Topics: Mice; Animals; Retinal Ganglion Cells; Beclin-1; Disease Models, Animal; Glaucoma; Apoptosis; Intraocular Pressure; Neuroserpin
PubMed: 36905120
DOI: 10.1016/j.ymthe.2023.03.008 -
Journal of the American Association For... Jan 2023Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, physiologic, hormonal, metabolic, and behavioral systems of all animals,... (Review)
Review
Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, physiologic, hormonal, metabolic, and behavioral systems of all animals, including those used in research. These wide-ranging biologic effects of light are mediated by distinct photoreceptors, the melanopsin-containing intrinsically photosensitive retinal ganglion cells of the nonvisual system, which interact with the rods and cones of the conventional visual system. Here, we review the nature of light and circadian rhythms, current industry practices and standards, and our present understanding of the neurophysiology of the visual and nonvisual systems. We also consider the implications of this extrinsic factor for vivarium measurement, production, and technological application of light, and provide simple recommendations on artificial lighting for use by regulatory authorities, lighting manufacturers, designers, engineers, researchers, and research animal care staff that ensure best practices for optimizing animal health and wellbeing and, ultimately, improving scientific outcomes.
Topics: Animals; Lighting; Retinal Ganglion Cells; Photoreceptor Cells; Circadian Rhythm
PubMed: 36755210
DOI: 10.30802/AALAS-JAALAS-23-000003 -
Developmental Dynamics : An Official... Feb 2022The coordinated wiring of neurons, glia and endothelial cells into neurovascular units is critical for central nervous system development. This is best exemplified in...
BACKGROUND
The coordinated wiring of neurons, glia and endothelial cells into neurovascular units is critical for central nervous system development. This is best exemplified in the mammalian retina where interneurons, astrocytes and retinal ganglion cells sculpt their vascular environment to meet the metabolic demands of visual function. Identifying the molecular networks that underlie neurovascular unit formation is an important step towards a deeper understanding of nervous system development and function.
RESULTS
Here, we report that cell-to-cell mTORC1-signaling is essential for neurovascular unit formation during mouse retinal development. Using a conditional knockout approach we demonstrate that reduced mTORC1 activity in asymmetrically positioned retinal ganglion cells induces a delay in postnatal vascular network formation in addition to the production of rudimentary and tortuous vessel networks in adult animals. The severity of this vascular phenotype is directly correlated to the degree of mTORC1 down regulation within the neighboring retinal ganglion cell population.
CONCLUSIONS
This study establishes a cell nonautonomous role for mTORC1-signaling during retinal development. These findings contribute to our current understanding of neurovascular unit formation and demonstrate how ganglion cells actively sculpt their local environment to ensure that the retina is perfused with an appropriate supply of oxygen and nutrients.
Topics: Animals; Endothelial Cells; Mammals; Mechanistic Target of Rapamycin Complex 1; Mice; Retina; Retinal Diseases; Retinal Ganglion Cells
PubMed: 34148274
DOI: 10.1002/dvdy.389