C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183484 | GEO | 2021/09/07
REPOSITORIES: GEO
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Project description:Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, type 2 and type 3, forms. We studied the two fly GBA1 orthologs, GBA1a and GBA1b. Each contains a Minos element insertion, which truncates its coding sequence. In the GBA1am/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, GBA1bm/m mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. GBA1bm/m mutant flies showed activation of the Unfolded Protein Response (UPR) and presented inflammation and neuroinflammation that culminated in development of a neuronopathic disease. Treatment with ambroxol did not rescue GCase activity or reduce substrate accumulation; however, it ameliorated UPR, inflammation and neuroinflammation, and increased life span. Our results highlight the resemblance between the phenotype of the GBA1bm/m mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities.
2021-03-31 | GSE142144 | GEO
Project description:The GBA1 gene encodes the lysosomal enzyme acid-β-glucocerebrosidase (GCase). GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD) and are a genetic risk factor for Parkinson´s disease (PD). Many GBA1 mutations cause aberrant GCase folding and processing but how these impinge on PD pathogenesis remains unclear. We addressed GCase functions in human dopaminergic (DA) neurons derived from engineered GBA1-deficient (GBA1-/-) embryonic stem cells (hESCs) and GBA1N370S PD patient-derived induced pluripotent cells (hiPSCs). GBA1-mutant DA neurons displayed aberrant morphologies and gene expression that were rescued by recombinant GCase treatment. GBA1-/- neurons have hyperactive Calcineurin (CaN) and nuclear localization of the Transcription Factor EB (TFEB). Expression of TFEB targets and lysosomal CLEAR network components were increased in GBA1-/- DA neurons and rescued by GCase replacement and CaN inhibition. Our findings reveal a link between increased CaN activity and loss of GCase, providing a mechanism for the disturbed lysosomal/autophagy pathways in GBA1-associated PD.
2022-12-31 | GSE118511 | GEO
Project description:Gaucher disease (GD) is characterized by the presence of glucosylceramide-laden macrophages (Gaucher cells) as the result of deficiency in the lysosomal hydrolase glucocerebrosidase (GBA). Non-neuronopathic type 1 GD is effectively treated by infusions with macrophage-targeted recombinant glucocerebrosidase. We here report how LC-MSE analysis of the proteome of laser-dissected splenic Gaucher cells revealed high expression of several proteins amongst which was gpNMB. This was confirmed by histochemistry and RNA quantification. Macrophages produce gpNMB as membrane protein but release soluble fragments. In plasma of symptomatic Gaucher patients (n=59) soluble gpNMB was next found to be on average 25-fold increased prior to treatment, without overlap with control values, (control mean: 20 ng/ml; range 11-34 ng/ml vs. GD mean: 495 ng/ml; range: 137-1283 ng/ml).
2016-09-27 | PXD001598 | Pride
Project description:Gaucher Disease (GD) is caused by defective glucocerebrosidase (GCase) activity and the consequent accumulation of its substrate, glucosylceramide (GC). This excess of accumulation of GC leads to broad functional impairments in multiple organs, but the pathogenic pathways leading to lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal function is obscure. To understand the molecular pathogenesis of GD, developmental global gene expression was conducted by microarray analyses of total mRNAs from lung and liver of two distinct GCase point-mutated mice (V394L/V394L and D409V/null) and genetic background matched wild-type controls. INFg regulated pro-inflammatory and IL-4 regulated anti-inflammatory cytokine/mediator network were constructed in the lung and liver of GCase mutant mice. Progressive alterations of the INFg and IL-4 pathways were similar, but to different degrees, in visceral tissues from the two different GCase mutated mice. These analyses implicate IFNg regulated pro-inflammatory and IL-4 regulated anti-inflammatory networks in the differential pathophysiological progression.
2011-08-02 | GSE23408 | GEO
Project description:In non-neuronopathic type 1 Gaucher disease (GD1) mutations in GBA1 gene results in deficiency of glucocerebrosidase and the accumulation of glucocerebroside in lysosomes of mononuclear phagocytes. The metabolic defect leads to a complex phenotype involving the viscera, the bone marrow and the skeleton. However the prevailing macrophage-centric view of the disease does not explain emerging aspects of the disease such as hematological malignancies, autoimmune diathesis, ParkinsonM-bM-^@M-^Ys disease and osteoporosis poorly responsive to macrophage targeted enzyme therapy or anti-resorptive therapies. We developed a conditional KO mouse model of GD1 to delineate cells and pathways in GD1. By targeting the cells of the hematopoetic and mesenchymal cell lineages through an Mx1 promoter, we recapitulated human GD1. We show that, in addition to significant visceral and hematologic disease, GD1 mice show profound osteopenia due to a bone formation defect. Cytokine measurements, microarray analysis and cellular immunophenotyping together point to widespread dysfunction of macrophages and other immune cells together with a striking abnormality in thymic T-cell development. Our study provides the first direct evidence for the involvement of cell lineages other than mononuclear phagocytes, most notably osteoblasts and T cells, in the pathophysiology of the clinical spectrum of type 1 GD. These findings have important implications for treatment of GD1. We hypothesize that regulation of gene expression is different in Gaucher disease compared with the normal controls. This difference may even be evident in the different stages of this disease. In order to gain insight to the genes that are potentially involved in the development of Gaucher disease in its different clinical stages, exon-array is chosen for this genome-wide association studies. Mouse liver and spleen samples from normal control, GD with moderate to severe splenomegaly/hepatomegaly, together nine samples were chosen. The goal is to find out genes of which the expression may relate to the GD or the severity of GD and thus help identify genetic modifier genes that may contribute to the onset and development of Gaucher disease.
2010-07-29 | E-GEOD-23086 | biostudies-arrayexpress
Project description:Gaucher Disease (GD) is caused by defective glucocerebrosidase (GCase) activity and the consequent accumulation of its substrate, glucosylceramide (GC). This excess of accumulation of GC leads to broad functional impairments in multiple organs, but the pathogenic pathways leading to lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal function is obscure. To understand the molecular pathogenesis of GD, developmental global gene expression was conducted by microarray analyses of total mRNAs from lung and liver of two distinct GCase point-mutated mice (V394L/V394L and D409V/null) and genetic background matched wild-type controls. INFg regulated pro-inflammatory and IL-4 regulated anti-inflammatory cytokine/mediator network were constructed in the lung and liver of GCase mutant mice. Progressive alterations of the INFg and IL-4 pathways were similar, but to different degrees, in visceral tissues from the two different GCase mutated mice. These analyses implicate IFNg regulated pro-inflammatory and IL-4 regulated anti-inflammatory networks in the differential pathophysiological progression. In order to understand the molecular pathogenesis of GD, the disease progression in those models were inverstigated in two visceral tissues (lung and liver) at four time points according to the genotypes. 9V/null: 4 weeks (4w), 12 weeks (12w), 18 weeks (18w), 28 weeks (28w); 4L: weeks (4w), 12 weeks (12w), 18 weeks (18w), 28 weeks (28w). The data from those models were analyzed relative to the adult wild type at 28 weeks.
2011-08-01 | E-GEOD-23408 | biostudies-arrayexpress
Project description:Mutations in the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher´s disease, are the most frequent genetic risk factor for Parkinson’s disease (PD). Here, we employed single-cell genomic approaches in induced pluripotent stem cell (iPSC)-derived midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration.
2023-03-06 | GSE198033 | GEO
Project description:Gene expression data obtained from induced pluripotent stem cells derived from wild type fibroblasts (iPSc WT) and from Gaucher Disease type 2 fibroblasts (GD iPSc). Also, gene expression analysis from the initial fibroblasts was made (WT fibroblasts and GD- fibroblasts), as well as gene expression analysis from a human embryonic stem cell line (hES4). Two different iPSc cell lines derived from Gaucher Disease type 2 fibroblasts were analysed in order to be compared to iPSc derived from Wild Type fibroblasts (only one cell line) and human embryonic stem cells (only one cell line). The initial cells: two different wild type fibroblasts and one Gaucher disease type 2 fibroblasts were also analysed.
2012-12-07 | E-GEOD-41243 | biostudies-arrayexpress
Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela- treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks. To understand the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela).
2013-09-07 | E-GEOD-44640 | biostudies-arrayexpress
Project description:Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher’s disease (GD), are the strongest genetic risk factor for Parkinson’s disease (PD) known to date. To elucidate the mechanisms underlying neurodegeneration in these patients, we generated induced pluripotent stem cells from subjects with GD and PD harboring GBA1 mutations and differentiated them to midbrain dopaminergic neurons. Highly enriched neurons showed a reduction of glucocerebrosidase activity and protein levels, increased glucosylceramide and α-synuclein levels and autophagic/lysosomal defects. Quantitative proteomics profiling revealed an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. We found dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium in mutant neurons. Importantly, correction of the mutations rescued such pathological phenotypes. Our findings provide evidence for a link between GBA1 mutations and complex changes in autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration.
2014-06-03 | PXD000866 | Pride