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Chronic chemogenetic activation of the superior colliculus in glaucomatous mice: local and retrograde molecular signature

ABSTRACT: One important facet of the glaucoma pathology is axonal damage, which ultimately disrupts the connection between the retina and its postsynaptic targets. The concurrent loss of retrograde support interferes with the functionality and survival of the retinal ganglion cells (RGCs). Con-versely, previous research has shown that stimulation of neuronal activity in a primary retinal target area—i.e., the superior colliculus— promotes RGC survival in an acute mouse model of glaucoma. To build further on this observation, we applied repeated chemogenetics in the superior colliculus of a more chronic model of glaucoma—i.e., the microbead occlusion model—and per-formed bulk RNA sequencing on collicular lysates and isolated RGCs. Our study revealed that chronic target stimulation upon glaucomatous injury phenocopies the a priori expected molecular response: growth factors were pinpointed as essential transcriptional regulators both in the locally stimulated tissue and in distant, unstimulated RGCs. Strikingly, and although the RGC tran-scriptome revealed an enrichment of pro-survival signaling pathways, functional rescue of injured RGCs was not achieved.

ORGANISM(S): Mus musculus

PROVIDER: GSE202012 | GEO | 2022/06/15

REPOSITORIES: GEO

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NMNAT2 Is Downregulated in Glaucomatous RGCs and RGC-Specific Gene Therapy with NMNAT2 Overexpression Rescues Glaucomatous Neurodegeneration and Visual Function

Project description:The lack of neuroprotective treatments for retinal ganglion cells (RGCs) and optic nerve (ON) is a central challenge for glaucoma management. Emerging evidence suggests that redox factor NAD+ decline is a hallmark of aging and neurodegenerative diseases including glaucoma. Supplementation with NAD+ precursors and overexpression of the nicotinamide mononucleotide adenylyltransferase (NMNAT), the key enzyme involved in the NAD+ biosynthetic process, have significant neuroprotection effect on glaucoma. Among the three NMNAT isoforms, only NMNAT2 is enriched in neurons, especially in axons, however, its role in glaucoma is not well studied. Here we present the expression levels of the enzymes that involved in NAD+ metabolism in both naïve and glaucomatous mouse RGCs. Intriguingly, NMNAT2 is the dominant form of NMNATs in RGCs and only its mRNA level, but not NMNAT1 or NMNAT3, is significant decreased in glaucomatous RGCs. We then demonstrated proof-of-principal gene therapy strategy of restoring RGC-specific NMNAT2 and NAD+ levels by AAV2-mediated RGC-specific promoter mSncg-driven long half-life NMNAT2 mutant. This gene therapy strategy is further tested in two optic neuropathy models, traumatic ON crush model and ocular hypertension glaucoma model. RGC-specific NMNAT2 overexpression significantly promotes RGC somata and axons survival and preserves visual function in both models. Our studies suggest that the weaking of NMNAT2 expression in glaucomatous RGCs contributes to detrimental NAD+ decline and that modulating RGC intrinsic NMNAT2 level by AAV2-mSncg vector is a potent gene therapy for glaucomatous neuroprotection.

2021-08-22 | GSE182483 | GEO

Global gene expression changes in rat retinal ganglion cells after experimental glaucoma

Project description:Goals of the study: 1. Assess the gene expression profile in rat RGC after experimental IOP elevation to elucidate the molecular mechanisms of RGC death. 2. Identify potentially novel genes and pathways that may contribute to RGC death in glaucoma. Background: Glaucoma is a neurodegenerative disease characterized by the slow, progressive degeneration of RGC. Elevated IOP is the biggest risk factor for developing glaucoma, loss of RGC and optic nerve atrophy. The pathophysiology of glaucomatous neurodegeneration is not fully understood. It is now clear that RGC die by apoptosis in glaucoma. However, what triggers the apoptosis is still unknown. So far, several gene expression studies have been performed on the retina as a whole. These studies revealed up and downregulation of many genes in response to elevated IOP and optic nerve transection. However, the retina is a complex tissue composed of neuronal, glial and vascular cell types. The RGCs only comprise 5% or less of retinal cells. The gene expression profiles from whole retina can not represent of RGC gene expression. In the current study, we sought to investigate the whole genome regulation of the RGCs in glaucoma. The study was carried out in 3 adult male Brown Norway rats with experimental glaucoma. An equal number of RGCs were captured from normal eyes and eyes with elevated IOP. Gene expression in the glaucomatous RGC was compared with that in the fellow RGC by using Affymetrix Gene chip.

2010-10-01 | E-GEOD-12596 | biostudies-arrayexpress

Amacrine cells suppress retinal ganglion cells survival and optic nerve regeneration bu releasing intersynaptic zinc

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Differential gene expression and pathway analysis by RNA sequencing in human OPTN(E50K) astrocytes

Project description:Retinal ganglion cell (RGC) degeneration is a primary characteristic of glaucoma, although non-cell autonomous mechanisms have been implicated in RGC dysfunction. Astrocytes closely associate with RGCs in the nerve fiber layer of the retina and optic nerve, where they can contribute to RGC neurodegeneration. However, the mechanisms by which astrocytes promote neurotoxicity and contribute to glaucoma remain unclear. Here we present data describing disease phenotypes in astrocytes and their ability to modulate RGC health.

2021-04-23 | GSE173129 | GEO

Retinal ganglion cell survival after severe optic nerve injury is modulated by crosstalk between JAK/STAT signaling and innate immune responses in the zebrafish retina

Project description:The death of retinal ganglion cells(RGC) after the damage on optic nerve as a result of high intraocular pressure is the main reason of the irreversible blindness in glaucoma patients ,and mammals have very limited ability of maintaining the RGCs after optic nerve injury.Zebrafish,however,possess the ability of keep most RGCs from death after optic nerve injury. The purpose of this study is to determine which gene or pathway mediate the RGC survival mechanism underlying.It is observed JAK/STAT signaling pathway as well as the innate immune response is activated after optic nerve injury(in this study,optic nerve transection).Pharmacological inhibition of JAK/STAT by intravitreal(IV) injection of JAK inhibitor,P6,induced the reduction of RGC survival while both local and systemic immune suppressor application result in the rescue of RGC survival.Moreover,phospho-STAT3(pSTAT3),which is an evidence of STAT3 activation,demonstrated elevation of expression level after ONT,and the trend of pSTAT3 expression change is consistent with the RGC survival rate change .JAK inhibition reduced pSTAT3 expression level and immune suppressor application elevated the pSTAT3 expression level on RGCs. In summary,these data suggested JAK/STAT signaling pathway crosstalk with innate immune response create a dynamic balance in the mechanism of RGC survival.Interestingly,innate immune response which was used to be considered promoting tissue repair in other studies,proved to be suppressing RGC survival in this study.These data could be used as reference for future direction of neuroprotection in glaucoma treatment.

2021-10-05 | GSE171426 | GEO

Global gene expression changes in rat retinal ganglion cells after experimental glaucoma

2010-10-01 | GSE12596 | GEO

Direct-induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplant in vivo

Project description:Since retinal ganglion cells (RGCs) do not regenerate after injury, RGC replacement therapy could provide an approach to vision restoration in glaucoma and other optic neuropathies. Here we developed a rapid protocol for direct induction of RGC (iRGC) differentiation from human iPSCs and ESCs in less than two weeks, by overexpression of NGN2 in RGC survival-promoting medium supplemented with a Notch inhibitor. Neuronal morphology and neurite growth were observed within one week of induction. Immunostaining and qRT-PCR for characteristic RGC-specific genes confirmed identity. Calcium imaging was used to evaluate iRGCs’ electrophysiologic maturation, and demonstrated GABA-induced excitatory calcium influx characteristic of immature RGCs. Using single cell-RNA sequencing (scRNA-seq) we further delineated iRGCs’ differentiation and compared iRGC transcriptomic profiles to fetal human and retinal organoid-derived RGCs. Unbiased clustering showed high similarities of transcriptomic profiles among iRGCs, early-stage fetal human RGCs and early-stage retinal organoid-derived RGCs. However, for some markers, including BRN3a, BRN3b and NEFL, iRGCs demonstrated expression patterns more similar to fetal RGCs than to retinal organoid RGCs. After intravitreal injection into rodent eyes, transplanted iRGCs survived and migrated into host retinas where they were detected one week and one month after transplant. Prior optic nerve trauma to the recipient host did not significantly enhance or detract from iRGC integration, but iRGCs protected host RGCs from neurodegeneration. Taken together, these data demonstrate rapid iRGC generation in vitro into an immature cell with high similarity to human fetal RGCs and capacity for retinal integration after transplant, including after optic nerve injury. The simplicity of this system may benefit translational studies on human RGCs.

2022-04-10 | GSE200452 | GEO

Intercellular communication atlas reveals Oprm1 as a neuroprotective factor for retinal ganglion cells

Project description:The neuronal cell death results in neurodegenerative diseases. The extracellular environment plays a critical role in regulating cell viability. In this study, we explore how intercellular communication contributes to the survival of retinal ganglion cells (RGCs) following the optic nerve crush (ONC). By performing single-cell RNA-seq on whole retinal cells, we observed transcriptomic responses in non-RGC retinal cells to the injury, with astrocytes and Müller glia having the most interactions with RGCs. By comparing the RGC subclasses showing distinct resilience cell death, we identified top 47 interactions that are stronger in the high-survival RGCs, likely representing neuroprotective interactions. We performed functional assays on one of the receptors, Mu-opioid receptor (Oprm1). Although Oprm1 is preferentially expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs), its neuroprotective effect could be transferred to multiple RGC subclasses by specific overexpressing Oprm1 in pan-RGCs. Our study provides an atlas of cell-cell interactions in both intact and post-ONC retina and an effective strategy to predict molecular mechanisms in neuroprotection, underlying the principal role played by extracellular environment in supporting neuron survival.

2023-10-01 | GSE241268 | GEO

Transcriptomic profiles of retinal ganglion cells are defined by the magnitude of intraocular pressure elevation in adult mice

Project description:Elevated intraocular pressure (IOP) is the major risk factor for glaucoma, a sight threatening disease of retinal ganglion cells (RGCs) and their axons. Despite the central importance of IOP, details of the impact of IOP elevation on RGC gene expression remain elusive. We developed a novel 4-step immunopanning protocol to extract adult mouse RGCs with high fidelity and used it to isolate RGCs from wild type mice exposed to 2 weeks of IOP elevation generated by the microbead model. IOP was elevated to 2 distinct levels which were defined as Mild (IOP increase >1mmHg and <4mmHg) and Moderate (IOP increase > 4mmHg). RNA sequencing was used to compare the transcriptional environment at each IOP level. Differentially expressed genes were markedly different between the 2 groups, and pathway analysis revealed frequently opposed responses between the IOP levels. These results suggest that the magnitude of IOP elevation has a critical impact on RGC transcriptional changes. Furthermore, it is possible that an IOP-based set point exists within RGCs to impact the direction of transcriptional change. It is possible that this improved understanding of changes in RGC gene expression can ultimately lead to novel diagnostics and therapeutics for glaucoma.

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Single Cell Transcriptome Analysis of Regenerating RGCs Reveals Potent Glaucoma Neural Repair Genes [Second_batch_sur_RGCs]

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2022-08-20 | GSE206625 | GEO

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