Comparison of Glaucoma-Relevant Transcriptomic Datasets Identifies Novel Drug Targets for Retinal Ganglion Cell Neuroprotection

Glaucoma is a leading cause of blindness and is characterized by the progressive dysfunction and irreversible death of retinal ganglion cells. We aimed to identify shared differentially expressed genes (DE genes) between different glaucoma relevant models of retinal ganglion cell injury using existing RNA-sequencing data, thereby discovering targets for neuroprotective therapies. A comparison of DE genes from publicly available transcriptomic datasets identified 12 shared DE genes. The Comparative Toxicogenomics Database (CTD) was screened for compounds targeting a significant proportion of the identified DE genes. Forty compounds were identified in the CTD that interact with >50% of these shared DE genes. We next validated this approach by testing select compounds for an effect on retinal ganglion cell survival using a mouse retinal explant model. Folic acid, genistein, SB-431542, valproic acid, and WY-14643 (pirinixic acid) were tested. Folic acid, valproic acid, and WY-14643 demonstrated significant protection against retinal ganglion cell death in this model. The increasing prevalence of open access-omics data presents a resource to discover targets for future therapeutic investigation.

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Dynamic Expression of HDAC3 in db/db Mouse RGCs and Its Relationship with Apoptosis and Autophagy

Journal of Diabetes Research ◽

10.1155/2020/6086780 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuhong Fu ◽

Ying Wang ◽

Xinyuan Gao ◽

Huiyao Li ◽

Yue Yuan

Keyword(s):

Diabetic Retinopathy ◽

Ganglion Cell ◽

Retinal Ganglion Cells ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Control Group ◽

Diabetic Patients ◽

Retinal Ganglion ◽

Glucose Levels ◽

Dynamic Expression

Background. Diabetic retinopathy (DR) is a severe complication of diabetes mellitus. DR is considered as a neurovascular disease. Retinal ganglion cell (RGC) loss plays an important role in the vision function disorder of diabetic patients. Histone deacetylase3 (HDAC3) is closely related to injury repair and nerve regeneration. The correlation between HDAC3 and retinal ganglion cells in diabetic retinopathy is still unclear yet. Methods. To investigate the chronological sequence of the abnormalities of retinal ganglion cells in diabetic retinopathy, we choose 15 male db/db mice (aged 8 weeks, 12 weeks, 16 weeks, 18 weeks, and 25 weeks; each group had 3 mice) as diabetic groups and 3 male db/m mice (aged 8 weeks) as the control group. In this study, we examined the morphological and immunohistochemical changes of HDAC3, Caspase3, and LC3B in a sequential manner by characterizing the process of retinal ganglion cell variation. Results. Blood glucose levels and body weights of db/db mice were significantly higher than that of the control group, P<0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (r=0.7424), P<0.01. HDAC3 was positively correlated with LC3B expression (r=0.7336), P<0.01. Discussion. We clarified the dynamic expression changes of HDAC3, Caspase3, and LC3B in retinal ganglion cells of db/db mice. Our results suggest the HDAC3 expression has a positive correlation with apoptosis and autophagy.

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Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma

Scientific Reports ◽

10.1038/s41598-021-01077-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Michal Geva ◽

Noga Gershoni-Emek ◽

Luana Naia ◽

Philip Ly ◽

Sandra Mota ◽

...

Keyword(s):

Ganglion Cell ◽

Retinal Degeneration ◽

Retinal Ganglion Cells ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Neuroprotective Effect ◽

Retinal Ganglion ◽

Cell Degeneration ◽

Sigma 1 Receptor ◽

Sigma 1

AbstractOptic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

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Bicycronic construct for optogenetic prosthesis of ganglion cell receptive field of degenerated retina

Доклады Академии наук ◽

10.31857/s0869-56524862258-261 ◽

2019 ◽

Vol 486 (2) ◽

pp. 258-261

Author(s):

L. E. Petrovskaya ◽

M. V. Roshchin ◽

G. R. Smirnova ◽

D. E. Kolotova ◽

P. M. Balaban ◽

...

Keyword(s):

Receptive Field ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Distinctive Feature ◽

Action Potentials ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Light Stimulation ◽

Genetic Construct ◽

Stimulation Of

For the purpose of optogenetic prosthetics of the receptive field of the retinal ganglion cell, we have created a bicistronic genetic construct that carries genes of excitatory (channelorhodopsin2) and inhibitory (anionic channelorhodopsin) rhodopsins. A distinctive feature of this construct is the combination of two genes into one construct with the mutant IRES inserted between them, which ensures precise ratio of the expression levels of the first and second gene in each transfected cell. It was found that the illumination of the central part of transfected neuron with light with a wavelength of 470 nm causes the generation of action potentials in the cell. At the same time, light stimulation of the periphery of the neuron causes cessation of the generation of action potentials. Thus, we were able to simulate the ON-OFF interaction of the receptive field of the retinal ganglion cell using optogenetic methods. Theoretically, this construction can be used for optogenetic prosthetics of degenerative retina in case of its delivery to ganglion cells using lentiviral vectors.

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All Brn3 genes can promote retinal ganglion cell differentiation in the chick

Development ◽

10.1242/dev.127.15.3237 ◽

2000 ◽

Vol 127 (15) ◽

pp. 3237-3247 ◽

Cited By ~ 2

Author(s):

W. Liu ◽

S.L. Khare ◽

X. Liang ◽

M.A. Peters ◽

X. Liu ◽

...

Keyword(s):

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Cell Development ◽

Large Set ◽

Retinal Ganglion ◽

Pou Domain ◽

Temporal Expression Pattern ◽

Cell Genesis

Targeted gene disruption studies in the mouse have demonstrated crucial roles for the Brn3 POU domain transcription factor genes, Brn3a, Brn3b, Brn3c (now called Pou4f1, Pou4f2, Pou4f3, respectively) in sensorineural development and survival. During mouse retinogenesis, the Brn3b gene is expressed in a large set of postmitotic ganglion cell precursors and is required for their early and terminal differentiation. In contrast, the Brn3a and Brn3c genes, which are expressed later in ganglion cells, appear to be dispensable for ganglion cell development. To understand the mechanism that causes the functional differences of Brn3 genes in retinal development, we employed a gain-of-function approach in the chick embryo. We find that Brn3b(l) and Brn3b(s), the two isoforms encoded by the Brn3b gene, as well as Brn3a and Brn3c all have similar DNA-binding and transactivating activities. We further find that the POU domain is minimally required for these activities. Consequently, we show that all these Brn3 proteins have a similar ability to promote development of ganglion cells when ectopically expressed in retinal progenitors. During chick retinogenesis, cBrn3c instead of cBrn3b exhibits a spatial and temporal expression pattern characteristic of ganglion cell genesis and its misexpression can also increase ganglion cell production. Based on these data, we propose that all Brn3 factors are capable of promoting retinal ganglion cell development, and that this potential may be limited by the order of expression in vivo.

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Gadd45α affects retinal ganglion cell injury in chronic ocular hypertension rats by regulating p38MAPK pathway

Gene ◽

10.1016/j.gene.2020.145030 ◽

2020 ◽

Vol 763 ◽

pp. 145030

Author(s):

Rui-Xue Sun ◽

Zhao-Hui Sun ◽

Qian Ren ◽

Li Li ◽

Li Yin ◽

...

Keyword(s):

Ganglion Cell ◽

Ocular Hypertension ◽

Retinal Ganglion Cell ◽

Cell Injury ◽

Retinal Ganglion ◽

P38mapk Pathway

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Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma

Brain Communications ◽

10.1093/braincomms/fcz035 ◽

2019 ◽

Vol 1 (1) ◽

Cited By ~ 5

Author(s):

James R Tribble ◽

Asta Vasalauskaite ◽

Tony Redmond ◽

Robert D Young ◽

Shoaib Hassan ◽

...

Keyword(s):

Electron Microscopy ◽

Animal Models ◽

Ganglion Cell ◽

Retinal Ganglion Cells ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Face Scanning ◽

Block Face ◽

Scanning Electron

Abstract Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. However, the earliest degenerative events that occur in human glaucoma are relatively unknown. Work in animal models has demonstrated that retinal ganglion cell dendrites remodel and atrophy prior to the loss of the cell soma. Whether this occurs in human glaucoma has yet to be elucidated. Serial block face scanning electron microscopy is well established as a method to determine neuronal connectivity at high resolution but so far has only been performed in normal retina from animal models. To assess the structure–function relationship of early human glaucomatous neurodegeneration, regions of inner retina assessed to have none-to-moderate loss of retinal ganglion cell number were processed using serial block face scanning electron microscopy (n = 4 normal retinas, n = 4 glaucoma retinas). This allowed detailed 3D reconstruction of retinal ganglion cells and their intracellular components at a nanometre scale. In our datasets, retinal ganglion cell dendrites degenerate early in human glaucoma, with remodelling and redistribution of the mitochondria. We assessed the relationship between visual sensitivity and retinal ganglion cell density and discovered that this only partially conformed to predicted models of structure–function relationships, which may be affected by these early neurodegenerative changes. In this study, human glaucomatous retinal ganglion cells demonstrate compartmentalized degenerative changes as observed in animal models. Importantly, in these models, many of these changes have been demonstrated to be reversible, increasing the likelihood of translation to viable therapies for human glaucoma.

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Neuroprotective and Anti-Inflammatory Effects of a Hydrophilic Saffron Extract in a Model of Glaucoma

International Journal of Molecular Sciences ◽

10.3390/ijms20174110 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4110 ◽

Cited By ~ 11

Author(s):

Jose A. Fernández-Albarral ◽

Ana I. Ramírez ◽

Rosa de Hoz ◽

Nerea López-Villarín ◽

Elena Salobrar-García ◽

...

Keyword(s):

Cell Death ◽

Intraocular Pressure ◽

Ganglion Cell ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Saffron Extract ◽

Anti Inflammatory ◽

Ganglion Cell Death

Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs). An increase in the intraocular pressure is the principal risk factor for such loss, but controlling this pressure does not always prevent glaucomatous damage. Activation of immune cells resident in the retina (microglia) may contribute to RGC death. Thus, a substance with anti-inflammatory activity may protect against RGC degeneration. This study investigated the neuroprotective and anti-inflammatory effects of a hydrophilic saffron extract standardized to 3% crocin content in a mouse model of unilateral, laser-induced ocular hypertension (OHT). Treatment with saffron extract decreased microglion numbers and morphological signs of their activation, including soma size and process retraction, both in OHT and in contralateral eyes. Saffron extract treatment also partially reversed OHT-induced down-regulation of P2RY12. In addition, the extract prevented retinal ganglion cell death in OHT eyes. Oral administration of saffron extract was able to decrease the neuroinflammation associated with increased intraocular pressure, preventing retinal ganglion cell death. Our findings indicate that saffron extract may exert a protective effect in glaucomatous pathology.

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Brn3b/Brn3c double knockout mice reveal an unsuspected role for Brn3c in retinal ganglion cell axon outgrowth

Development ◽

10.1242/dev.129.2.467 ◽

2002 ◽

Vol 129 (2) ◽

pp. 467-477 ◽

Cited By ~ 2

Author(s):

Steven W. Wang ◽

Xiuqian Mu ◽

William J. Bowers ◽

Dong-Seob Kim ◽

Daniel J. Plas ◽

...

Keyword(s):

Cell Differentiation ◽

Ganglion Cell ◽

Retinal Ganglion Cells ◽

Retinal Ganglion Cell ◽

Knockout Mice ◽

Ganglion Cells ◽

Axon Outgrowth ◽

Retinal Ganglion ◽

Double Knockout ◽

Ganglion Cell Axon

In mice, Brn3 POU domain transcription factors play essential roles in the differentiation and survival of projection neurons within the retina, inner ear, dorsal root and trigeminal ganglia. During retinal ganglion cell differentiation, Brn3b is expressed first, followed by Brn3a and Brn3c. Targeted deletion of Brn3b, but not Brn3a or Brn3c, leads to a loss of most retinal ganglion cells before birth. However, as a few retinal ganglion cells are still present in Brn3b–/– mice, Brn3a and Brn3c may partially compensate for the loss of Brn3b. To examine the role of Brn3c in retinal ganglion cell development, we generated Brn3b/Brn3c double knockout mice and analyzed their retinas and optic chiasms. Retinal ganglion cell axons from double knockout mice were more severely affected than were those from Brn3b-deficient mice, indicating that Brn3c was required for retinal ganglion cell differentiation and could partially compensate for the loss of Brn3b. Moreover, Brn3c had functions in retinal ganglion cell differentiation separate from those of Brn3b. Ipsilateral and misrouted projections at the optic chiasm were overproduced in Brn3b–/– mice but missing were entirely in optic chiasms of Brn3b/Brn3c double knockout mice, suggesting that Brn3c controlled ipsilateral axon production. Forced expression of Brn3c in Brn3b–/– retinal explants restored neurite outgrowth, demonstrating that Brn3c could promote axon outgrowth in the absence of Brn3b. Our results reveal a complex genetic relationship between Brn3b and Brn3c in regulating the retinal ganglion cell axon outgrowth.

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