Clusterin is protective for liver fibrosis through mesothelial-specific LRP2 receptor mediated endocytosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE235221 | GEO | 2024/06/01
REPOSITORIES: GEO
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Project description:Clusterin is protective for liver fibrosis through mesothelial-specific LRP2 receptor mediated endocytosis
| PRJNA985580 | 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 one of the most significant genetic risk factors for late onset Alzheimer’s disease. Numerous studies have now demonstrated that CLU-AD mutations and amyloid-β (Aβ) treatment alter the trafficking and localisation of glycosylated CLU. iPSCs with altered CLU trafficking were generated following the removal of CLU exon 2 by CRISPR/Cas9 gene editing. Neurons were generated from control, unedited and exon 2 -/- iPSCs and were incubated with aggregated Aβ peptides. Changes in cell death and neurite length were quantified to determine if altered CLU protein trafficking influenced neuronal sensitivity to Aβ.
2022-07-05 | GSE207466 | GEO
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:Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impedes astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPCs differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.
2024-08-23 | GSE275514 | 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: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:Disease causal mechanism remains largely unknown for most Alzheimer’s disease (AD) genome-wide association studies (GWAS) risk loci, including the Clusterin (CLU) locus. Here, leveraging our approach to identify functional GWAS risk variants that show allele-specific open chromatin (ASoC), we nominated a putative AD causal SNP rs1532278 (T/C) of CLU that showed strong ASoC specifically in iPSC-derived excitatory neurons (iGlut). We found the AD protective allele T of rs1532278 elevated neuronal CLU and promoted neuron excitability. Transcriptomic analysis of iGlut (T/T vs. C/C) co-cultured with mouse astrocytes surprisingly showed allele T upregulated lipid synthesis and astrocytic lipid metabolism pathways. Further corroborative functional studies mechanistically tied allele T to CLU-facilitated neuron-glia lipid transfer and astrocytic lipid droplet (LD) formation. Interestingly, astrocytes with more LD were found to uptake less glutamate likely due to reactive oxygen species (ROS), which may contribute to CLU-promoted neuron excitability. Our study uncovered a previously unappreciated protective role of neuronal CLU in maintaining proper neuronal excitability through lipid-mediated neuron-glia communication.
2024-06-10 | GSE269153 | GEO