ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE247360 | GEO | 2024/01/17
REPOSITORIES: GEO
Similar Datasets
Project description:Carrying premature termination codons in one allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute or chronic conditions. When the acute inflammation was induced through peripheral lipopolysaccharide (LPS) injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished pro-inflammatory responses by impairing CD14 expression in the brain.
2019-10-31 | GSE139592 | GEO
Project description:Mitochondrial diseases (MD) are a group of inherited diseases with highly varied and complex clinical presentations and their molecular diagnosis has been improved through next generation sequencing. Here, we report four individuals, two of whom are siblings, affected by a progressive mitochondrial encephalopathy who carry biallelic variants in the cardiolipin biosynthesis gene CRLS1. Using patient fibroblasts, we characterised defects in mitochondrial function that were reflective of CRLS1 dysfunctions, providing functional evidence that the CRLS1 I109N variant causes the MD phenotype observed in this patient. Lipid profiling highlighted that the CRLS1 variants reduced cardiolipin levels, altered its acyl-chain composition and caused a significant increase in phosphatidylglycerol, the substrate of cardiolipin synthase. Proteomic profiling of patient cells and Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. Our findings support that deleterious variants in CRLS1 cause a novel autosomal recessive MD, presenting as a severe encephalopathy with multisystemic involvement. Furthermore, we have identified key changes in cardiolipin and proteome profiles across various degrees of cardiolipin dysfunction, facilitating future advances in diagnostic technologies based on curated signatures in high-throughput datasets.
2023-03-06 | PXD029861 | Pride
Project description:Autophagy supervises proteostasis and survival of plasma cells. TFG (Trk-fused gene) promotes autophagosome-lysosome flux in murine CH12 B cells, as well as their survival. Moreover, TFG is abundant in plasma cells. Hence, quantitative proteomics of CH12tfgKO and WT B cells in combination with lysosomal inhibition via NH4Cl should identify proteins that are prone to lysosomal degradation and contribute to autophagy, plasma cell biology and B cell survival. While lysosome inhibition via NH4Cl treatment unexpectedly reduced a number of proteins, it increased a large cluster of translational and ribosomal proteins, independent of TFG. The prosurvival protein BCL10 was decreased in CH12tfgKO B cells while the immunoglobulin JCHAIN was increased. Gene ontology analysis revealed that proteins 39 regulated by TFG alone, or in concert with lysosomes, localize to mitochondria and membrane 40 bounded organelles. Likewise, TFG regulated the abundance of metabolic enzymes, such as the glycolytic enzyme ALDOC and the short chain fatty acid activating enzyme ACOT9. To test for a function of TFG in lipid metabolism we performed shotgun lipidomics of glycerophospholipids. Total phosphatidylglycerol was more abundant in CH12tfgKO B cells. In contrast, several glycerophospholipid species, such as 36:2 phosphatidylethanolamine and 36:2 phosphatidylinositol, showed a dysequilibrium. Addition of phosphatidylglycerol elevated Cardiolipin in B cells. Hence, we propose a role for TFG in the regulation of proteins involved in survival and plasma cell biology, as well as in lipid homeostasis, mitochondrial functions and metabolism.
2024-02-27 | PXD039180 | Pride
Project description:Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin-remodeling, upon loss of the cardiolipin acyl transferase Tafazzin, mutes HIF-1a signaling in hypoxia. Tafazzin-deficiency does not affect posttranslational HIF-1a regulation but rather HIF-1a gene-expression, a dysfunction recapitulated in iPSCs-derived cardiomyocytes from Barth Syndrome patients with Tafazzin-deficiency. RNAseq analyses confirmed drastically altered signaling in Tafazzin mutant cells. In hypoxia, Tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-kB activation and concomitantly HIF-1a gene-expression. In agreement, Tafazzin-deficient mice hearts display reduced HIF-1a levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin-remodeling dampens HIF-1a signaling through inactivation of a non-canonical signaling pathway: Lack of NF-kB activation through reduced mitochondrial ROS production diminishes HIF-1a transcription.
2018-09-12 | GSE119775 | GEO
Project description:The granulin (GRN) gene stands out as a prominent player in frontotemporal degeneration (FTD). Progranulin (PGRN) is a protein encoded by the GRN gene. Mutations in the GRN gene leading to PGRN deficiency are associated with lysosomal storage diseases and various neurodegenerative diseases. Despite the significance of GRN function, the specific impact of GRN-/- condition on diverse biomolecules such as proteins, lipids, and metabolites remain unclear. This study employs a multi-omics approach, integrating proteomics, lipidomics, and metabolomics analyses for comprehensively unraveling the molecular alterations by GRN-/- condition. Proteins, lipids, and metabolites were obtained from the same sample using a single extraction method. Our result reveals distinct molecular profiles between iPSC and neurons, emphasizing upregulated synaptic proteins such as SYN1, SYT1, VAMP2, and SV2A in proteomics, decreased cardiolipin (CL) containing 16:0 and 18:1 acyl chain in lipidomics, and shifts in acetylcholine and amino acid in metabolomics. Furthermore, the GRN-/- condition induces significant alterations across the proteome, lipidome, and metabolome of induced pluripotent stem cells (iPSC) and iPSC-derived neurons, unveiling unique metabolic pathways. Although this study was conducted at a whole cell level, this comprehensive perspective contributes to our understanding of the intricate interplay among proteins, lipids, and metabolites in neurodevelopment and neurodegenerative diseases.
2023-11-13 | MSV000093388 | MassIVE
Project description:DJ1 KO was generated in BJsips iPSC and differentiated into midbrain organoids with the respective iPSC controls. The midbrain organoids were collected at day 40, 100 and 200 after differentiation.
2022-09-06 | ST002327 | MetabolomicsWorkbench
Project description:Pancreatic cancer stem cells (PCSCs) characterize the pancreatic ductal adenocarcinomas (PDAC) and play a key role in driving their poor outcomes and resistance to targeted therapies. Although advanced proteomics and lipidomics technology facilitates quantitation of intracellular proteins and lipids, little is known about the regulation of signalling and metabolic pathways in PCSCs. Here we shown that PCSCs, derived from different PDAC cell lines, have specific and common proteome and lipidome modulations. PCSCs displayed down-regulation of L-lactate dehydrogenase A chain (LDHA) and, more interestingly, upregulation of trifunctional enzyme subunit alpha (HADHA) which is involved in cardiolipin remodelling. The upregulated proteins of PCSCs were mainly involved in fatty acid (FA) elongation and biosynthesis of unsaturated FAs. Accordingly, lipidomics revealed a general increase of FAs 18:1, 20:2, 20:3, and 20:4, which are products of the catalytic activity of fatty acid elongase-5 (ELOVL5) predicted as common active gene of PCSCs. Moreover, in accordance with HADHA upregulation, lipidomics also showed the induction in PCSCs of molecular species of cardiolipin with mixed incorporation of 16:0, 18:1, and 18:2 acyl chains. Our data indicate a crucial role of fatty acid elongation and cardiolipin remodelling in PCSCs, which could therefore represent attractive targets to improve the therapeutic treatments of PDAC
2021-09-09 | PXD023069 | Pride
Project description:Here we show that synthesis of the mitochondrial phospholipid cardiolipin is an indispensable driver of thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response by overexpressing cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency diminishes mitochondrial uncoupling in brown and beige adipocytes and elicits a nuclear transcriptional response through ER stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake and renders animals strikingly insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin is a powerful regulator of organismal energy homeostasis through thermogenic fat bioenergetics.
2018-07-19 | GSE110297 | GEO
Project description:Abstract of associated manuscript: Daptomycin is the first of a new class of cyclic lipopeptide antibiotics used against multidrug-resistant Gram-positive pathogens. The proposed mechanism of action involves disruption of the functional integrity of the bacterial membrane in a Ca2+-dependent manner. We have used transcriptional profiling to demonstrate that treatment of Bacillus subtilis with daptomycin strongly induces the lia operon including the autoregulatory LiaRS two-component system (homologous to Staphylococcus aureus VraSR). The lia operon protects against daptomycin and deletion of liaH, encoding a phage shock protein A (PspA)-like protein, leads to 3-fold increased susceptibility. Since daptomycin interacts with the membrane, we tested mutants with altered membrane composition for effects on susceptibility. Deletion mutations of mprF (lacking lysyl-phosphatidylglycerol) or des (lipid desaturase) increased daptomycin susceptibility, whereas overexpression of MprF decreased susceptibility. Conversely, depletion of the cell for the anionic lipid phosphatidylglycerol led to increased resistance. Fluorescently-labeled daptomycin localized to the septa and in a helical pattern around the cell envelope and was delocalized upon depletion of phosphatidylglycerol. Together, these results indicate that the daptomycin-Ca2+ complex interacts preferentially with regions enriched in anionic phospholipids and leads to membrane stresses that can be ameliorated by PspA family proteins. Bacillus subtilis W168, WT (+DAP) vs. WT (-DAP). The experiment was conducted in triplicate using three independent total RNA preparations. For WT-rep1 and WT-rep2, daptomycin treated samples were labeled with Alexa Fluor 647 and untreated samples with Alexa Fluor 555. For WT-rep3, the daptomycin treated sample was labeled with Alexa Fluor 555 and the untreated sample with Alexa Fluor 647.
2008-12-10 | E-GEOD-13900 | biostudies-arrayexpress
Project description:Interventions: Patients with spleen deficiency and qi stagnation syndrome SDQSS:NA;Patients with DHS with damp-heat accumulation syndrome:NA;Patients with SPOS with stasis and internal resistance syndrome:NA;Patients with SKYDS of Spleen and Kidney Yang Deficiency Syndrome:NA;Patients with liver-kidney yin deficiency syndrome LKYDS:NA;QBDS patients with deficiency of both qi and blood syndrome:NA
Primary outcome(s): Serum metabolites;Fecal microbiome;lipidomics
Study Design: Diagnostic test for accuracy
| 105810 | ecrin-mdr-crc