Glycosylated clusterin species facilitate amyloid beta toxicity in human neurons.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA855866 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19977742_1.fastq.gz | Fastqsanger.gz | |||
| SRR19977742_2.fastq.gz | Fastqsanger.gz | |||
| SRR19977743_1.fastq.gz | Fastqsanger.gz | |||
| SRR19977743_2.fastq.gz | Fastqsanger.gz | |||
| SRR19977744_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 36 |
Similar Datasets
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 one of the most significant genetic risk factors for late onset Alzheimer's disease (AD). However, the mechanisms by which CLU contributes to AD development and pathogenesis remain unclear. Studies have demonstrated that the trafficking and localisation of glycosylated CLU proteins is altered by CLU-AD mutations and amyloid-β (Aβ), which may contribute to AD pathogenesis. However, the roles of non-glycosylated and glycosylated CLU proteins in mediating Aβ toxicity have not been studied in human neurons. iPSCs with altered CLU trafficking were generated following the removal of CLU exon 2 by CRISPR/Cas9 gene editing. Neurons were generated from control (CTR) and exon 2 -/- edited iPSCs and were incubated with aggregated Aβ peptides. Aβ induced changes in cell death and neurite length were quantified to determine if altered CLU protein trafficking influenced neuronal sensitivity to Aβ. Finally, RNA-Seq analysis was performed to identify key transcriptomic differences between CLU exon 2 -/- and CTR neurons. The removal of CLU exon 2, and the endoplasmic reticulum (ER)-signal peptide located within, abolished the presence of glycosylated CLU and increased the abundance of intracellular, non-glycosylated CLU. While non-glycosylated CLU levels were unaltered by Aβ25-35 treatment, the trafficking of glycosylated CLU was altered in control but not exon 2 -/- neurons. The latter also displayed partial protection against Aβ-induced cell death and neurite retraction. Transcriptome analysis identified downregulation of multiple extracellular matrix (ECM) related genes in exon 2 -/- neurons, potentially contributing to their reduced sensitivity to Aβ toxicity. This study identifies a crucial role of glycosylated CLU in facilitating Aβ toxicity in human neurons. The loss of these proteins reduced both, cell death and neurite damage, two key consequences of Aβ toxicity identified in the AD brain. Strikingly, transcriptomic differences between exon 2 -/- and control neurons were small, but a significant and consistent downregulation of ECM genes and pathways was identified in exon 2 -/- neurons. This may contribute to the reduced sensitivity of these neurons to Aβ, providing new mechanistic insights into Aβ pathologies and therapeutic targets for AD.
| S-EPMC9633591 | biostudies-literature
Project description:BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides
| PRJNA957689 | ENA
Project description:Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer’s disease (AD); however, the etiology of Abeta42 toxicity remains elusive. In a proteomic approach using a yeast model for intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated toxicity.
2022-04-27 | PXD012612 | 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:A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils
2025-01-17 | PXD059046 | Pride
Project description:Immunoglobulin light chain (LC) amyloidosis (AL) is one of the most common types of systemic amyloidosis. The lack of reliable in vivo models hinders the study of the disease in its physiological context. We developped a transgenic mouse model producing high amounts of a human AL free light chain (LC). While mice exceptionnaly develop spontaneous AL amyloidosis and do not exhibit organ toxicity due to the circulating amyloidogenic LC, a single injection of amyloid fibrils, made up of the variable domain (VL) of the human LC, or soluble VL led to amyloid deposits, mainly in heart. The biochemical composition and the fragmentation pattern of the LC in the fibrils are highly similar to that of human AL fibrils, arguing for a conserved mechanism of amyloid fibrils formation. Amyloidosis positive mice also develop an early cardiac dysfunction, with increased NT-proBNP, diastolic dysfunction and remodeling of the extracellular matrix. Overall, this transgenic mice closely reproduces human cardiac AL amyloidosis and shows that a partial degradation of the LC initiate amyloid fibril formations in vivo. Accumulation of AL amyloid fibrils, rather than the soluble LC, drive the initial cardiac dysfunction. This model fills an important gap for research on AL amyloidosis and preclinical evaluation of new therapies.
2025-01-17 | GSE286368 | GEO
Project description:Treatment strategies that are efficient against established Alzheimer's disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid b (Ab) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood-brain barrier (BBB) in age-matched wildtype mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes involved in cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology.
2024-09-25 | GSE263166 | GEO
Project description:Effects of intracellular amyloid toxicity on the transcriptome of MC65 human nerve cells
| PRJNA603004 | ENA
Project description:The conserved human secreted glycoprotein Clusterin (aka Apolipoprotein-J, ApoJ) is an abundant component of body fluids such as blood plasma and cerebrospinal fluid. Clusterin is thought to function as an extracellular molecular chaperone stabilizing misfolded proteins in solution. In addition, clusterin forms lipoprotein complexes and fractions with HDL particles in plasma. Variants of the clusterin gene constitute the third most important risk factor for late-onset Alzheimer's disease. To better understand it structure and functions, the crystal structure of a mutant form of Clusterin was determined. In order to validate the structural data, hydrogen-deuterium exchange kinetics followed by pepsin proteolysis and mass spectrometry analysis of recombinant mutant and wildtype protein were performed (Part 1 of the deposited data). Based on the structure, rational mutants were designed and subjected to functional tests such as chaperone activity, cellular uptake and receptor binding and lipoprotein complex formation. In order to probe the conformation of Clusterin in the lipoprotein complex, free and lipid-bound protein were subjected to limited proteolysis with chymotrypsin and the resultant fragments analyzed by LC/MS proteomics (Part 2 of the deposited data).
2025-07-22 | PXD057022 | Pride