TGFBR1 is an on-off switch for exosome-induced neuroprotection and visual function improvement
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE274213 | GEO | 2025/08/31
REPOSITORIES: GEO
Similar Datasets
Project description:TGFBR1 is an on-off switch for exosome-induced neuroprotection and visual function improvement
| PRJNA1145412 | ENA
Project description:Glaucoma is a group of optic neuropathies characterized by the progressive degeneration of retinal ganglion cells (RGCs) as well as their axons leading to irreversible loss of sight. Medical management of the intraocular pressure (IOP) still represents the gold standard in glaucoma therapy, which only manages a risk factor and does not directly address the neurodegenerative component of this eye disease. Recently, our group showed that antibody derived immunopeptides (encoding complementarity-determining regions, CDRs) provide attractive glaucoma medication candidates and directly interfere its pathogenic mechanisms by different modes of action. In accordance with these findings, the present study showed the synthetic CDR2 peptide (INSDGSSTSYADSVK) significantly increased the RGCs viability in vitro in a concentration-dependent manner (p < 0.05 using a CDR2 concentration of 50 µg/mL). Employing state-of the-art immunoprecipitation experiments, we confirmed that synthetic CDR2 exhibited a high affinity towards the retinal target protein histone H3.1 (HIST1H3A) (p < 0.001 and log2 fold change > 3). Furthermore, virtual docking analyses predicted potential CDR2-specific binding regions of HIST1H3A, which might represent essential PTM sites for epigenetic regulations. Quantitative MS analysis revealed that 39 proteins were significantly changed between CDR2-treated and untreated control retinae (p < 0.05). An up-regulation of proteins involved in the energy production (e.g., ATP5F1B and MT-CO2) as well as the regulatory ubiquitin proteasome system (e.g., PSMC5) was induced by the synthetic CDR2 peptide. On the other hand, metabolic key enzymes (e.g., DDAH1 and MAOB) as well as ER stress-related proteins (e.g., SEC22B and VCP) were found with low abundancy in CDR2-treated retinae and were also partially confirmed by microarray technology. Based on these findings, it can be hypothesized that the specific protein-peptide interaction influences the regulatory epigenetic function of HIST1H3A promoting the neuroprotective mechanism on RGCs in vitro. It also might serve as basis for a synergistic immunotherapy of glaucoma in the future.
2022-11-09 | PXD034046 | Pride
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
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
Project description:To gain a deeper insight into roles of Arid1a in injured retinal ganglion cells (RGCs), we performed ATAC-seq and RNA-seq to analyze the genome-wide changes of chromatin accessibility and transcriptome changes before and after Arid1a deletion in RGCs of the adult mouse using Cre-lox system.
2020-04-20 | GSE147844 | GEO
Project description:This study aimed to characterize the transcriptomes of adult retinal ganglion cells (RGCs). These cells were isolated through their expression of a TdTomato molecule that would only turn on when Cre was present. Cre was controlled by the Parvalbumin promoter.
2019-11-01 | GSE115332 | GEO
Project description:Numerous micro-RNAs (miRNAs) affect neurodevelopment and neuroprotection, but potential roles of many miRNAs in regulating these processes are still unknown. Here, we used the retinal ganglion cell (RGC) central nervous system (CNS) projection neuron and optic nerve crush (ONC) injury model, to optimize a mature miRNA arm-specific quantification method for characterizing the developmental regulation of miR-1247-5p in RGCs, investigated whether injury affects its expression, and tested whether upregulating miR-1247-5p-mimic in RGCs promotes neuroprotection and axon regeneration. We found that, miR-1247-5p is developmentally-downregulated in RGCs, and is also further downregulated after ONC. Importantly, RGC-specific upregulation of miR-1247-5p promoted neuroprotection and axon regeneration after injury in vivo. To gain insight into the underlying mechanisms, we analyzed by bulk-mRNA-seq embryonic and adult RGCs, along with adult RGCs transduced by miR-1247-5p-expressing viral vector, and identified developmentally-regulated cilial and mitochondrial biological processes, which were reinstated to their embryonic levels in adult RGCs by upregulation of miR-1247-5p. Because axon growth is also a developmentally-regulated process, in which mitochondrial dynamics play important roles, it is possible that miR-1247-5p promoted neuroprotection and axon regeneration through regulating mitochondrial functions.
2024-01-26 | GSE252514 | GEO
Project description:Numerous micro-RNAs (miRNAs) affect neurodevelopment and neuroprotection, but potential roles of many miRNAs in regulating these processes are still unknown. Here, we used the retinal ganglion cell (RGC) central nervous system (CNS) projection neuron and optic nerve crush (ONC) injury model, to optimize a mature miRNA arm-specific quantification method for characterizing the developmental regulation of miR-1247-5p in RGCs, investigated whether injury affects its expression, and tested whether upregulating miR-1247-5p-mimic in RGCs promotes neuroprotection and axon regeneration. We found that, miR-1247-5p is developmentally-downregulated in RGCs, and is also further downregulated after ONC. Importantly, RGC-specific upregulation of miR-1247-5p promoted neuroprotection and axon regeneration after injury in vivo. To gain insight into the underlying mechanisms, we analyzed by bulk-mRNA-seq embryonic and adult RGCs, along with adult RGCs transduced by miR-1247-5p-expressing viral vector, and identified developmentally-regulated cilial and mitochondrial biological processes, which were reinstated to their embryonic levels in adult RGCs by upregulation of miR-1247-5p. Because axon growth is also a developmentally-regulated process, in which mitochondrial dynamics play important roles, it is possible that miR-1247-5p promoted neuroprotection and axon regeneration through regulating mitochondrial functions.
2024-01-26 | GSE252516 | GEO
Project description:Rbfox1 is a splicing regulator that has been associated with various neurological conditions such as autism spectrum disorder, mental retardation, epilepsy, attention-deficit/hyperactivity disorder, and schizophrenia. We show that in adult rodent retinas, Rbfox1 is expressed in all types of retinal ganglion cells (RGCs) as well as in certain subsets of amacrine cells (ACs) within the inner nuclear and ganglion cell layers. In developing retinas, Rbfox1 can be detected as early as E12. At that age, Rbfox1 is localized in the cytoplasm of differentiated RGCs. Between P0 and P5, strong expression of Rbfox1 in the inner plexiform layer was observed. This coincided with switching of Rbfox1 localization in RGC somas from cytoplasmic to a predominantly nuclear. Dynamic changes in Rbfox1 expression during first 10 postnatal days are correlated with the stage II spontaneous retinal waves of excitation, which in mice begins around the time of birth and continues for as long as two weeks. By P10, dendritic staining of Rbfox1 was dramatically reduced and remained so in the fully developed retina. In Rbfox1 knockout (KO) animals no detectable changes in retinal gross morphology were observed two months after Rbfox1 downregulation. However, the visual cliff test revealed marked abnormalities of depth perception of these animals. Retinal transcriptome analysis of Rbfox1 KO mice identified a number of genes that are involved in establishing neural circuits and synaptic transmission, including Vamp1, Vamp2, Snap25, Trak2, and Slc1A7, suggesting a role of Rbfox1 in the regulation of genes that facilitate AC and RGC synaptic communication.
2018-07-19 | GSE105084 | GEO
Project description:Loss of retinal ganglion cells (RGCs) is central to the pathogenesis of optic neuropathies such as glaucoma. Increased cAMP signaling in RGCs is neuroprotective, as has been previously demonstrated in multiple animal models, including optic nerve crush (ONC) injury. We have shown that displacement of the cAMP-specific phosphodiesterase PDE4D3 from an RGC perinuclear compartment by expression of the modified PDE4D3 N-terminal peptide 4D3(E) increases perinuclear protein kinase A activity in cultured neurons and RGC survival in vivo after ONC injury. To explore potential mechanisms by which 4D3(E) expression promotes neuroprotection, mice intravitreally injected with an adeno-associated virus to express an mCherry-tagged 4D3(E) peptide were subjected to ONC injury and analyzed by single cell RNA-sequencing (scRNA-seq) for changes in RGC gene expression. 4D3(E)-mCherry expression was associated with an attenuation of injury-induced changes in gene expression, thereby supporting the hypothesis that enhanced perinuclear PKA signaling promotes neuroprotective RGC gene expression.
2024-08-28 | GSE260952 | GEO