Glycosylated clusterin species facilitate amyloid beta toxicity in human neurons.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE207466 | GEO | 2022/07/05
REPOSITORIES: GEO
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Project description:Glycosylated clusterin species facilitate amyloid beta toxicity in human neurons.
| PRJNA855866 | ENA
Project description:Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic-targeting agents such taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells upregulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdc2. In this study we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A but leads to relief of negative feedback inhibition and activation of Wee1-Cdc2 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU-regulated cell cycle effectors, like PP2A and Wee1, may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors Biological triplicate of PC3 treated with siClusterin were compared to biological trplicate of PC3 treated with siScramblein
2016-03-01 | E-GEOD-67256 | biostudies-arrayexpress
Project description:Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic-targeting agents such taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells upregulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdc2. In this study we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A but leads to relief of negative feedback inhibition and activation of Wee1-Cdc2 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU-regulated cell cycle effectors, like PP2A and Wee1, may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors
2016-03-01 | GSE67256 | GEO
Project description:We discovered “runner” plasma, collected from voluntarily running mice, infused into sedentary mice recapitulates the cellular and functional benefits of exercise on the adult brain. Importantly, runner plasma reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a striking increase in complement cascade inhibitors including clusterin (CLU), which is facilitating the anti-inflammatory effects of runner plasma. Intravenously injected CLU strongly binds to brain endothelial cells reducing their inflammatory gene expression in an acute model of brain inflammation and in Alzheimer’s disease model mice. These findings demonstrate the existence of anti-inflammatory “exercise factors” that are transferrable, target the cerebrovasculature and benefit the brain.
2021-09-01 | GSE164401 | GEO
Project description:Physical exercise seems universally beneficial to human and animal health, slowing cognitive aging and neurodegeneration. Cognitive benefits are tied to increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms mediating these effects. We discovered that “runner” plasma, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU), a central protein for the anti-inflammatory effects of runner plasma. Intravenously injected CLU strongly binds to brain endothelial cells reducing their inflammatory gene expression in an acute model of brain inflammation and in an Alzheimer’s disease mouse model. Cognitively impaired patients participating in structured exercise for 6 months had higher plasma clusterin levels. These findings demonstrate the existence of anti-inflammatory “exercise factors” that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans engaging in exercise.
2021-12-22 | PXD027406 | Pride
Project description:Physical exercise seems universally beneficial to human and animal health, slowing cognitive aging and neurodegeneration. Cognitive benefits are tied to increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms mediating these effects. We discovered “runner” plasma, collected from voluntarily running mice, infused into sedentary mice recapitulates the cellular and functional benefits of exercise on the adult brain. Importantly, runner plasma reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a striking increase in complement cascade inhibitors including clusterin (CLU), which is facilitating the anti-inflammatory effects of runner plasma. Intravenously injected CLU strongly binds to brain endothelial cells reducing their inflammatory gene expression in an acute model of brain inflammation and in Alzheimer’s disease model mice. Cognitively impaired patients participating in structured exercise for 6 months showed improved cognition and higher plasma clusterin levels. These findings demonstrate the existence of anti-inflammatory “exercise factors” that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans engaging in exercise.
2021-12-22 | PXD022262 | Pride
Project description:Clusterin has been indicated to protect human retinal pigment epithelial (RPE) cells from oxidative stress-induced apoptosis. This study was conducted to identify aberrantly expressed microRNAs (miRNAs) downstream clusterin in RPE cells.
2016-09-21 | GSE87115 | GEO
Project description:Alzheimer’s disease (AD) is the most common form of dementia and one of the leading causes of death in the United States. In past decades, extensive efforts have been devoted to improving our understanding of AD pathogenesis and accelerating biomarker discovery for early diagnosis and clinical treatment of AD. Herein, this study aims to quantify clusterin (CLU) and apolipoprotein E (APOE) in blood samples from AD patients and evaluate these two proteins as potential biomarkers in AD diagnosis. In-house synthesized 5-plex isotopic N,N-dimethyl leucine (iDiLeu) tags were used to label target peptide standards at different concentrations to construct standard curves. Our study reveals that the levels of CLU and APOE exhibit clear disparities in male vs. female AD groups but not in male vs. female non-AD groups, while the levels of serum CLU and APOE do not show statistical differences in the AD groups and non-AD groups. Principal component analysis (PCA) with CLU and APOE showed some separation between the AD and non-AD participants. Significance: Dissecting CLU and APOE heterogeneity in AD pathogenesis may therefore facilitate delineating the pathological relevance for specific pathways between different genders, leading to personalized medicine in the future. Collectively, this study introduces a cost-effective absolute quantitative proteomics strategy for target protein quantitation and lays the foundation for future investigation of CLU and APOE as potential biomarkers for AD.
2022-10-05 | PXD030724 | Pride
Project description:The mammalian SID-1 transmembrane family member 1 (SIDT1), are multi-pass transmembrane proteins that mediate the cellular uptake and intracellular trafficking of nucleic acids, playing important roles in the immune response and tumorigenesis. We here report N-glycosylation as a key regulator of SIDT1-mediated RNA transport activities. To identify regulators whose expression was induced by N-glycan-deficient SIDT1, we further performed gene expression analysis on wild-type SIDT1 and non-N-glycosylated SIDT1overexpression HEK293F cells. Samples were subjected to RNA sequencing (RNA-seq) to reveal genes differences in SIDT1 overexpressing cells versus SIDT1N-glycan overexpressing cells. Our results indicate that the non-N-glycosylated SIDT1 is severely misfolded. These severely misfolded non-N-glycosylated SIDT1 may cause ER stress, leading to the induction of the unfolded protein response (UPR) and regulated by the ERQC system.
2023-08-09 | GSE239877 | GEO
Project description:Alzheimers disease (AD) is the most common form of dementia in the elderly with no cure. Although huge efforts have been made to develop drugs for AD, most programs aimed for disease-modifying therapies have failed. Possible reasons for the high failure rate include insufficient understanding of mechanisms underlying AD pathogenesis. The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset AD. However, whether the CLU rs11136000 SNP is functional and what are molecular mechanisms underlying the risk effect of the CLU variant remain unknown. In this study, we identified the CLU rs11136000 SNP as a functional variant by CRIPSR/Cas9 knockout of the SNP. Moreover, by switching the risk C and the protective T alleles using CRISPR/Cas9 editing, we generated isogenic iPSCs with different alleles of the CLU rs11136000 SNP. Astrocytes derived from isogenic iPSCs carrying the C or T allele exhibited different CLU expression and differential inflammatory response. C/C astrocytes carrying two C alleles expressed higher level of CLU and exhibited elevated interferon (IFN) response and CXCL10 expression upon TNFalpha/IL1beta treatment. Furthermore, using human iPSC-derived astrocytes and OPCs co-cultured on nanofibers, we demonstrated that elevated CXCL10 expression in C/C astrocytes induced by TNFalpha/IL1beta led to inhibition of OPC proliferation and myelination. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk C allele carriers. This knowledge could help us to design more effective strategies to treat AD by targeting IFN response and CXCL10 that are upstream of myelination deficits, an early event in AD pathogenesis that proceeds before cognitive decline.
2022-01-07 | MSV000088660 | MassIVE