Disrupted Energy Metabolism is Associated with Retinal Ganglion Cell Degeneration in Autosomal Dominant Optic Atrophy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE292269 | GEO | 2026/01/06
REPOSITORIES: GEO
Dataset's files
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Similar Datasets
Project description:Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1’s highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
2025-05-07 | PXD059584 | Pride
Project description:Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1’s highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
2025-05-07 | PXD059645 | Pride
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
Project description:To explore the potential roles of WIF1 upregulation in glaucoma pathogenesis, we performed WIF1 overexpression in mouse retina via AAV delivery and then assessed its impact on IOP, retinal visual function, and RGC survival. We found it causes visual function defects and RGC loss, especially the RGCs from periphery retina. Our integrative analyses from single cell RNA-seq, ATAC-seq, and spatial transcriptomics have further uncovered the dynamic signaling changes from various retinal cells to RGCs. And our spatial transcriptomics results have also revealed the various changes of central and peripheral RGCs after WIF1 overexpression.
2025-05-09 | GSE293380 | GEO
Project description:To explore the potential roles of WIF1 upregulation in glaucoma pathogenesis, we performed WIF1 overexpression in mouse retina via AAV delivery and then assessed its impact on IOP, retinal visual function, and RGC survival. We found it causes visual function defects and RGC loss, especially the RGCs from periphery retina. Our integrative analyses from single cell RNA-seq, ATAC-seq, and spatial transcriptomics have further uncovered the dynamic signaling changes from various retinal cells to RGCs. And our spatial transcriptomics results have also revealed the various changes of central and peripheral RGCs after WIF1 overexpression.
2025-05-09 | GSE293381 | GEO
Project description:Retinal ganglion cells (RGCs) play a critical role in the transmission of visual signals from the retina to the brain required for proper vision. The optic neuropathies, including glaucoma, NAION, LHON, traumatic optic neuropathy, optic pathway glioma result in the reversible and irreversible changes in RGCs, ultimately leading to their death. RGC loss is permanent given that these cells cannot regenerate in mammals. Neuroregenerative strategies for managing optic neuropathies have mainly focused on restoring the lost RGC cell population in a glaucomatous retina. This treatment approach not only aims to halt disease progression, but also to restore the lost vision by replacing the damaged/lost RGCs through RGC transplantation. Significant strides have been made in this field of RGC transplantation and regeneration. As a first step of RGC transplantation, several protocols now exist to differentiate cells into primary RGCs, and several sources of donor RGC have been established including human ES and iPSC-derived RGCs. To achieve functional regeneration, the transplanted RGCs must survive, integrate, and extend their axons and establish connections within the retina and the brain. Of the many factors influencing initial donor RGCs survival, the innate immunity [ref] and primarily microglia reactivity is of particular interest. In ocular models of glaucoma, microglia have been heavily implicated in driving disease progression, promoting a pro-inflammatory environment. In some instances, activated microglia have been directly implicated in RGC loss by mediating phagocytosis of the damaged or injured RGCs. In line with this, our recent work, shows that activated host microglia are detrimental to donor RGCs, presumably via phagocytosis of the donor RGCs. We observed that pre-treatment of donor RGCs with FasL and annexin V to block the exposed phosphatidylserine residues of the stressed donor RGCs prior to transplantation reduced activation of host microglia, and better RGC survival rates post transplantation. Studies like these and others underscore the importance of modulating host microglia reactivity for better transplantation outcomes. To further improve donor RGC survival post transplantation, a better understanding of the host myeloid cell reactivity following donor RGC transplantation is paramount. We and others have previously shown the importance of modulating the retinal microenvironment to promote RGC survival. In the current study, we profiled the transcriptome of the host myeloid cell population (CX3CR1-GFP) using a single cell RNA sequencing approach, to delineate the myeloid cell population most relevant for donor RGC survival post transplantation. A focused analysis on the microglia cell population was performed, given their established role in glaucoma disease progression. In addition to profiling the expression pattern of the known classic microglia disease associated signatures such as ApoE, Spp1, and Lgals, we identified several other genes associated with, and or driving microglia activation, including Cybb, Atf3, Aurka and Kif22. Given the known function of these genes in other disease contexts, we believe that these genes are important for modulating donor RGC survival post transplantation, thus warrant further investigation in this context. Taken together, with reference to our established adult mouse retina cell atlas, we present a comprehensive analysis of the host myeloid cell population, specifically focusing on microglia reactivity status, at a single cell resolution level, providing insights into the regulatory mechanisms that may be important for donor RGC survival and integration into glaucomatous retina post transplantation.
2025-12-12 | GSE285564 | GEO
Project description:Retinal ganglion cells (RGCs) are the sole projection neurons that connect the eye with the brain, and the degeneration of these cells in diseases such as glaucoma results in vision loss or blindness. Similar to other neurons throughout the central nervous system, RGCs are postmitotic and therefore highly dependent upon autophagy to remove damaged proteins or organelles to maintain proper cellular homeostasis. Autophagy deficits have been implicated in multiple neurodegenerative diseases including glaucoma. In addition, a subpopulation of glaucoma patients possesses mutations in the autophagy receptor Optineurin (OPTN) resulting glaucoma within a normal range of intraocular pressure, with the OPTN(E50K) mutation known to induce a severe degeneration. Despite this, our knowledge of how autophagy impairment promotes neurodegeneration within RGCs remains limited. We advanced a human pluripotent stem cell (hPSC) model of RGC neurodegeneration with an underlying OPTN(E50K) mutation to study how autophagy disruption contributes to RGC neurodegeneration. We identified OPTN protein was reduced but accumulated within the somas in RGCs with the OPTN(E50K) mutation, and this accumulation was associated with a decrease in autophagic flux. To rule out the possibilities that the specificity of the antibody incapable to recognize E50K region resulting the reduction of OPTN protein, we performed proteomics analysis at week 2 hPSC-RGCs of post purification and identified 154 downregulated proteins as well as 178 upregulated proteins associated with OPTN(E50K) RGCs compared with isogenic controls. Taken together, we identified proteins that were altered by OPTN(E50K) mutation in RGCs, and which may provide potential mechanisms that contribute to RGC neurodegeneration.
2025-05-06 | PXD033173 | Pride
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.
2010-10-01 | GSE12596 | GEO
Project description:Background: As the sole output neurons for the retina, retinal ganglion cells (RGCs) transmit all visual information from the retina via the optic nerve to the brain. RGCs do not regenerate when injured, and effective therapies for promoting RGC survival and axon regeneration in optic neuropathies comprise an unmet clinical need, including in the common disease glaucoma. Histone deacetylases (HDACs) are epigenetic modifiers that repress gene transcription and play a key role in retinal development and disease. In this study, we identify the role of HDAC4 in RGC neurodegeneration and axon regeneration. Methods: The role of HDAC4 in the regulation of RGC neuroprotection and axon regeneration was studied in the mouse optic nerve crush (ONC) model for optic neuropathy by transduction of RGCs in vivo with adeno-associated virus (AAV) vectors. HDAC4- and ONC-dependent gene expression in vivo were studied by single cell RNA sequencing (scRNA-seq) of isolated RGCs. Results: A loss-of-function screen for the role of HDACs in RGC survival after optic nerve crush (ONC) injury identified HDAC4 as essential element for RGC survival. Accordingly, expression of a constitutively nuclear HDAC4 S246/467/632A missense mutant (3SA) increased RGC survival and axon regeneration after ONC injury. Similar beneficial effects were conferred by expression of an N-terminal fragment of HDAC4 (HDAC4 NT) that constitutively represses gene expression. scRNA-seq showed that one day after ONC injury, transcriptomic profiles of RGCs were altered such that HDAC4 NT and to a lesser degree the HDAC4 3SA mutant attenuated the gene expression changes associated with injury. Conclusions: This study demonstrates that enhancement of nuclear HDAC4 activity will promote RGC survival and axon regeneration in the ONC model of RGC injury, identifying HDAC4 as a novel target in the development of therapeutics for RGC protection and restoration of visual function.
2026-01-01 | GSE252860 | GEO
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