Evalutation of global gene expression changes in NGLY1 deficient mouse embryonic fibroblasts (MEF)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE121475 | GEO | 2019/12/31
REPOSITORIES: GEO
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Project description:Evalutation of global gene expression changes in NGLY1 deficient mouse embryonic fibroblasts (MEF)
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Project description:We report using a single-cell transcriptomic study of cerebral organiods (COs) developed from WA09 hESCs with gene editing-induced NGLY1 mutations and from NGLY1-deficient patient's hiPSCs at 40 or 80 days of development. WA09 hESC-derived COs with and without mutant NGLY1 and patient's hiPSC-derived COs with and without the ectopic expression NGLY1 were analyzed.
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Project description:The data includes a transcriptome analysis of K562 cell lines in which the gene N-glycanase 1 (NGLY1) was mutated in exon 1 and/or exon 3 to include loss of function mutations as described in Mueller and Jakob et al, 2020. The data were used in conjunction with whole proteome MS/MS experiments to show a gene expression profile consistent with NGLY1 deficiency, a human disease. The experiments demonstrate the wide ranging effect of the loss of NGLY1 on a cellular system.
2020-04-20 | E-MTAB-8876 | biostudies-arrayexpress
Project description:In the biological systems, several genes are involved in protein glycosylation and deglycosylation pathways. Congenital disorders of deglycosylation (CDDG) are a set of disorders which occur due to the defect in genes involved in deglycosylation pathways. The only known CDDG so far is the defect in N-glycanase 1 (NGLY1), which primary function is to cleave the N-glycans from misfolded proteins prior to their proteasomal degradation. We used TMT-based N-glycoproteomics and proteomics on patient derived NGLY1 deficient and control fibroblasts to characterize the alteration in glycoproteome and proteome. 24 fractions of enriched glycopeptides after size exclusion chromatography (SEC) and 24 fractions after basic reverse phase liquid chromatography (bRPLC) were analyzed by LC-MS/MS for glycoproteomics and proteomics, respectively. We identified a total of 3,255 N-glycopeptides which were quantified on 550 glycosylation sites of 407 glycoproteins. A site specific aberrant glycosylation was observed for several extracellular matrix and cell adhesion proteins. By using quantitative proteomics, we detected 8,041 proteins. The alteration in expression of several proteins separated the affected individuals and controls. This is the first glycoproteomic study in patient derived NGLY1-CDDG fibroblasts. The glycoproteomics and proteomics analysis in NGLY1-CDDG provides the potential biomarkers and will increase our general understanding of its pathogenesis.
2023-05-10 | PXD034364 | Pride
Project description:Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy and seizures. NGLY1’s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons, but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.
2025-02-13 | GSE197454 | GEO
Project description:NGlY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the NGLY1 gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder, and liver dysfunction. To better understand disease pathogensis and neurological symptoms of NGLY1 deficiency we generated and characterized midbrain organoids using patient-derived iPSCs from two patients with disease causing mutations.
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Project description:ING1b and GADD45a are nuclear proteins involved in the regulation of cell growth, apoptosis and DNA repair. We found that ING1b and GADD45a physically and functionally interact in the epigenetic regulation of specific target genes. In order to study this interaction further, we analysed the transcriptional changes in MEF cells from single and double Ing1/Gadd45 knockout mice via microarray profiling. Mouse embryonic fibroblasts (MEF cells) were isolated from embryonic day E15.5 male embryos, either wild-type (WT) or knockout for Ing1 (Ing1-/-), Gadd45a (Gadd45a-/-) or Ing1/Gadd45a (double knockout, DKO), and cultured for 3 passages. Samples were then collected in duplicates per MEF line for expression array profiling.
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Project description:N-glycanase 1(NGLY1) catalyzes the removal of N-linked glycans from newly synthesized or misfolded protein to exert protein quality control function via the process of endoplasmic reticulum-associated degradation (ERAD). NGLY1 deficiency (OMIM 615273) is a newly diagnosed rare genetic disorder with ~60 patients worldwide to date. The affected individuals present a broad spectrum of clinical features, including developmental delay, seizures, muscle weakness, liver failure, and the reduced secretion of sweats and tears. Recent studies explored several possible molecular mechanisms of NGLY1 deficiency including in vivo proteostasis, mitochondrial homeostasis, innate immunity, water and ion transport, with the goal of linking these findings to the pathophysiology of the disease. This study focuses on the dysregulation of ERAD in NGLY1 deficiency. We demonstrate the abnormal accumulation of ERAD substrates in NGLY1 deficient cells. Comprehensive global quantitative proteomics discovered elevated levels of novel endogenous proteins in NGLY1 defective human and mouse cells. Further biological validation assays confirmed the altered abundance of several key candidates’ that were observed in the isobarically labeled proteomic experiments. CCN2 was selected for further analysis due to its high fold change in different cell models of NGLY1 deficiency. Functional assays show elevated CCN2 and over-stimulated TGF-β signaling in NGLY1 deficient cells. Given the important role of CCN2 and TGF-β pathway in mediating systemic fibrosis, we propose a potential link of increased CCN2 and TGF-β signaling to microscopic liver fibrosis in NGLY1 patients.
2021-12-21 | PXD026301 | Pride
Project description:Raw files from LWAC-based glycopeptide enrichment and ubiquitin enrichment from MEF wild type, Ngly1-KO, Engase-KO, and Ngly1/Engase-KO cells.
| MSV000084330 | MassIVE