Immune Tolerance to HSP60 Attenuates Neurodegeneration in Glaucoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1119479 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR29270210_1.fastq.gz | Fastqsanger.gz | |||
| SRR29270210_2.fastq.gz | Fastqsanger.gz | |||
| SRR29270212_1.fastq.gz | Fastqsanger.gz | |||
| SRR29270212_2.fastq.gz | Fastqsanger.gz |
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Project description:Our previous study suggests that CD4+ T cells primed by bacterial heat shock proteins (HSP) mediate an autoimmune mechanism contributing to the pathogenesis of glaucoma. The present study showed that the activity of CD4+ T cells from the peripheral blood mononuclear cells (PBMC) of POAG patients was significantly higher than control subjects as revealed by single-cell RNA sequencing. The notion of antigenic mimicry between gut bacteria and mouse HSPs expressed in the eye causes glaucomatous degeneration remains unclear. Here, we report that the induction of immune tolerance by nasal administration of bacterial HSP60 protein led to an increase in regulatory T (Tr1) cells and suppression of HSP-specific Th1 cell frequencies in glaucoma mice. leading to protections against retinal ganglion cell loss and preservation of spatial vision in glaucoma mice. Moreover, this neuroprotective effect on retinal ganglion cells in HSP-immune-tolerant mice was compromised by IL-10 deficiency. Our data suggests that induction of immune tolerance to HSP60 presents a potential therapeutic strategy protecting against retinal degeneration and vision loss in glaucoma by partial restoration of T cell-mediated immune balance. Detailed information: https://github.com/mcrewcow/PBMC_Glaucoma_human CellXGene web-browser: https://cellxgene.cziscience.com/collections/de2cde16-c8d3-4a6d-80be-1be9e879aaca
2025-06-11 | GSE268936 | GEO
Project description:To investigate the immediate effect of HSP60 dysfunction on mitochondrial functions, we induced the expression of a dominant-negative ATPase-deficient HSP60 mutant (HSP60-D423A) in HEK293 cells using tetracycline . Incorporation of HSP60-D423A subunits into HSP60 heptamer rings leads to dysfunction of the chaperonin complex. We titrated tetracycline levels to have a biologically relevant cellular model that can be monitored over time. Expression of the HSP60-D432A protein resulted in significantly reduced cell counts at 72 hours induction compared to uninduced and HSP60-WT co-expressing cells. To study the effects of onset of HSP60 deficiency, we monitored transcriptional changes using RNASeq.
2024-09-27 | GSE254495 | 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:To identify regulatory responses that could give clues as to the cause(s) of the growth arrest observed in E. coli cells expressing mutant Hsp60-(p.Val98Ile) and Hsp10 versus cells expressing wild type Hsp60 and Hsp10, we performed microarray analyses. We reasoned that the decreased chaperonin activity of the Hsp60-(p.Val98Ile) protein would greatly impair or abolish folding of E. coli proteins that depend on chaperonin assistance. The resulting decreased levels of various activities may cause compensatory up-regulation or deregulation of genes. The transcriptomes of cells shifted to expression of the arabinose-inducible chaperonin operon with either the Hsp60-(p.Val98Ile) mutant or the wild type Hsp60 from the second plasmid were compared. RNA samples from three independent cultures expressing the mutant or two independent cultures expressing wild type Hsp60 were pooled, respectively. Keywords: Comparison of cells expressing two different variants of Hsp60
2008-04-14 | GSE10974 | GEO
Project description:To identify regulatory responses that could give clues as to the cause(s) of the growth arrest observed in E. coli cells expressing mutant Hsp60-(p.Val98Ile) and Hsp10 versus cells expressing wild type Hsp60 and Hsp10, we performed microarray analyses. We reasoned that the decreased chaperonin activity of the Hsp60-(p.Val98Ile) protein would greatly impair or abolish folding of E. coli proteins that depend on chaperonin assistance. The resulting decreased levels of various activities may cause compensatory up-regulation or deregulation of genes. The transcriptomes of cells shifted to expression of the arabinose-inducible chaperonin operon with either the Hsp60-(p.Val98Ile) mutant or the wild type Hsp60 from the second plasmid were compared. RNA samples from three independent cultures expressing the mutant or two independent cultures expressing wild type Hsp60 were pooled, respectively. Experiment Overall Design: B178 (groELS)-deleted cells double-transformed with two plasmids harboring an IPTG-inducible operon with wild type human Hsp60 and Hsp10 and a second plasmid harboring an arabinose inducible operon with either Hsp60-(p.Val98Ile) and Hsp10 (mutant cells) or wild type Hsp60 and Hsp10 (wild type cells) were grown in dYT medium (21) supplemented with kanamycin (10 mg/L), ampicillin (100 mg/L) and IPTG (0.1mM) at 30°C in a shaking water bath. At OD536 â?? 0.1 bacteria were harvested by centrifugation at ambient temperature, resuspended in fresh medium, and 0.2% arabinose was added. Growth was continued at 30°C. After 10 hours 3ml samples were withdrawn and RNA was isolated. Experiment Overall Design: Two independent transformant clones of the wild type cells and three of the mutant cells were grown in this way. The RNA preps from the 2 wild type and the three mutant cells, respectively, were pooled, cDNA was synthesized, labelled and subjected to Affymetrix arrays.
2008-06-11 | E-GEOD-10974 | biostudies-arrayexpress
Project description:Neuroinflammation is a crucial process for the loss of retinal ganglion cells (RGC), a major characteristic of glaucoma. High expression of high mobility group box protein 1 (HMGB1) plays a detrimental role in inflammatory processes and is elevated in the retinas of glaucoma patients. Therefore, this study aimed to investigate the effects of intravitreal injection of an anti-HMGB1 monoclonal antibody (anti-HMGB1 Ab) in an experimental animal model of glaucoma. Two groups of Spraque Dawley rats received episcleral vein occlusion to chronically elevate intraocular pressure (IOP): (1) IgG group, intravitreal injection of an unspecific IgG as a control, n=5, (2) HMGB1 group, intravitreal injection of an anti-HMGB1 Ab, n=6. IOP, retinal nerve fiber layer thickness (RNFLT), and the retinal flash response was monitored longitudinally. Post-mortem examinations included immunohistochemistry, microarray, and mass spectrometric analysis. RNFLT was significantly increased in the HMGB1 group compared to the IgG group (p<0.001). RGC density showed improved neuronal cell survival in the retina in HMGB1 compared to the IgG group (p<0.01). Mass spectrometric proteomic analysis of retinal tissue showed increased abundance of RNA metabolism-associated heterogeneous nuclear ribonucleoproteins (hnRNPs), such as hnRNP U, D, and H2, in animals injected with the anti-HMGB1 Ab, indicating that application of the antibody may cause increased gene expression. Microarray analysis showed significantly decreased expression of C-X-C motif chemokine ligand 8 (CXCL8, p<0.05) and connective tissue growth factor (CTGF, p<0.01) in the HMGB1 group. Thus, these data suggest that intravitreal injection of anti-HMGB1 Ab reduced HMGB1-dependent inflammatory signaling and mediated RGC neuroprotection.
2022-05-20 | PXD031987 | Pride
Project description:Modelling HSP60 deficiency using an inducible transgenic HSP60 ATPase deficient mutant
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Project description:To investigate the immediate effect of HSP60 dysfunction on mitochondrial functions, we induced the expression of a dominant-negative ATPase-deficient HSP60 mutant (HSP60-D423A) in HEK293 cells using tetracycline . Incorporation of HSP60-D423A subunits into HSP60 heptamer rings leads to dysfunction of the chaperonin complex. We titrated tetracycline levels to have a biologically relevant cellular model that can be monitored over time. Expression of the HSP60-D432A protein resulted in significantly reduced cell counts at 72 hours induction compared to uninduced and HSP60-WT co-expressing cells. To study the effects of onset of HSP60 deficiency, we monitored the proteomics changes using TMT based proteomics.
2025-05-06 | PXD048918 | 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