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Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

ABSTRACT: In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. To constrain the model we used transcriptomics, and proteomics data, which we obtained from healthy controls and Refsum disease patient fibroblasts incubated with phytol, a precursor of phytanic acid. Using this model, we investigated the metabolic phenotype of Refsum disease at the genome-scale, and we studied the effect of phytanic acid on cell metabolism. We identified 20 metabolites that were predicted to discriminate between Healthy and Refsum disease patients, several of which with a link to amino acid metabolism.

OTHER RELATED OMICS DATASETS IN: PXD015518

ORGANISM(S): Homo sapiens

PROVIDER: GSE138379 | GEO | 2020/03/21

REPOSITORIES: GEO

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A fibroblast-specific genome-scale model focused on fatty acid alpha-oxidation

Project description:Refsum disease is an inborn error of metabolism that is characterized by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. After clinical suspicion of this disorder, including progressive retinitis pigmentosa and polyneuropathy, Refsum disease is biochemically diagnosed by elevated levels of phytanic acid in plasma and tissues of the patient. To date, no cure exists for Refsum disease, but phytanic acid levels in patients can be reduced by plasmapheresis and a strict diet. In recent years, computational models have become valuable tools to provide insight into the complex behaviour of metabolic networks. Besides the comprehensive models that contain all known metabolic reactions within the human body, several tissue- and cell-type-specific models have been developed. However, while systems biology approaches are widely used for complex diseases, only few studies have been published for inborn errors of metabolism. In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics, exo-metabolomics, and proteomics data, which we obtained from healthy controls and Refsum disease patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanic acid and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of Refsum disease at the genome scale, and we studied the effect of phytanic acid on cell metabolism. We identified 20 metabolites that were predicted to discriminate between Healthy and Refsum’s Disease patients, whereof several with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.

2020-03-20 | PXD015518 | Pride

Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

Project description:Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

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Gene expression profile of sporadic and PSEN1 early-onset Alzheimer’s Disease

Project description:Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease. 21 Samples were analyzed: 7 controls, 7 Early-onset Alzheimer's disease (AD) patients and 7 early-onset AD genetically determined by a mutation in PSEN1 gene.

2015-01-20 | E-GEOD-39420 | biostudies-arrayexpress

The landscape of immune cells in the mouse HCC model with F1 and F3 subtype

Project description:In this study, we identified and validated a molecular classification of hepatocellular carcinoma (HCC) patients based on 42 fatty acid degradation (FAD) genes. The F1 subtype was characterized by the lowest expression of FAD genes, whereas F3 subtype had the highest expression levels, and F2 had the intermediate expression levels of FAD genes. We characterized the immune microenvironment in HCC patients from different FAD subtypes. To further explore the immune landscape of HCC, we generated the Nras-driven HCC model (belonging to the F1 subtype) and the Akt1-driven HCC model (belonging to the F3 subtype) by hydrodynamic tail vein injection (HTVi) of oncogenes together with the sleeping beauty transposase. The tumor tissues were resected from the liver 14 weeks after the hydrodynamic delivery of the plasmids, isolated for single cells, and prepared for scRNA-seq.

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Transcription profiling of inguinal lymph nodes from rats injected with pristane, phytol, both pristane and phytol or untreated to obtain a molecular understanding of the protective effects of phytol on pristane induced arthritis

Project description:Comparison of gene expression in inguinal lymph nodes in four groups of rats; one with induced arthritis by injection with pristane, one injected with phytol, one injected with both pristane and phytol, and one untreated group. The objective was to obtain a molecular understanding of the protective effects of phytol on pristane induced arthritis (PIA). The animals were sacrificed close to disease onset, i.e. ten days after administration.

2007-12-31 | E-MEXP-782 | biostudies-arrayexpress

Transcriptome analysis of N140fs and T141_L142delinsMISLISV mutations in the zebrafish orthologue of the Alzheimer's disease gene PSEN2

Project description:Alzheimer’s disease is the most common form of age-related dementia. At least 15 mutations in the human gene PRESENILIN 2 (PSEN2) have been found to cause familial Alzheimer’s disease (fAD). Zebrafish possess an orthologous gene, psen2, and present opportunities for investigation of PRESENILIN function related to Alzheimer’s disease. The most prevalent and best characterized fAD mutation in PSEN2 is N141I. The equivalent codon in zebrafish psen2 is N140. We used genome editing technology in zebrafish to target generation of mutations to the N140 codon. We isolated two mutations: psen2N140fs, causing truncation of the coding sequence, and psen2T141_L142delinsMISLISV, that deletes the two codons immediately downstream of N140 and replaces them with seven codons coding for amino acid residues MISLISV. Thus, like almost every fAD mutation in the PRESENILIN genes, this latter mutation does not truncate the gene’s open reading frame.

2020-09-19 | GSE158233 | GEO

Gene expression profile of sporadic and PSEN1 early-onset Alzheimer’s Disease

2015-01-20 | GSE39420 | GEO

Vitamin B2 enables PPARa regulation of fasting glucose availability

Project description:Flavin adenine dinucleotide (FAD) mediates oxidation-reduction reactions required for cellular energy demands. Fatty acid oxidation (FAO) disorders caused by flavoprotein mutations and FAD depletion disrupt energy balance and glucose production during fasting. These FAO disorders are difficult to manage clinically, and their biochemical pathogenesis is poorly understood. Here, we identify a mechanistic connection between FAD levels and hepatic glucose production. Depleting the FAD pool in mice with a vitamin B2 deficient diet (B2D) resulted in phenotypes associated with organic acidemia phenotypes, including reduced body weight and whole-body fat oxidation rates coupled with hypoglycemia. Integrated discovery approaches revealed that B2D broadly tempered fasting activation of target genes for the nuclear receptor PPARa, including those required for gluconeogenesis. Consistent with this, Ppara knockout depleted liver FAD levels and worsened B2D hepatic glucose production. Treatment with the PPARa agonist fenofibrate overcame B2D phenotypes and rescued glucose availability and fatty liver signatures through activation of the integrated stress response and refilling anaplerotic amino acid substrates for glucose production. We conclude that PPARa governs metabolic responses to FAD availability and suggest pharmacologic activation as a strategy for treating disorders of riboflavin and FAD deficiency.

2022-06-18 | GSE206200 | GEO

Characterization of the LFR Genomic Islet in Staphylococcus aureus CC30

Project description:We report the application of RNA-Seq to assess transcriptional profiles of S. aureus CC30 strains with allelic replacements (knockouts) of two genes in the LFR genomic islet: 1) fatty acid desaturase (fad) and 2) a MocR regulator. The overall results of our study suggest that the LFR islet enhances metabolic plasticity of the CC30 lineage which contributes to increased colonization, survival and persistence in the host. The background strain used for these experiments was UAMS-1. Allelic replacements of fad and MocR were made in UAMS-1. The RNA-Seq experiments compared the transcriptional profiles of UAMS-1 vs. delta fad, and UAMS-1 vs. delta MocR. Two biological replicates were used for each RNA-Seq analysis.

2016-07-05 | E-GEOD-83995 | biostudies-arrayexpress

Mitochondrial anomalies in induced pluripotent stem cells from Alzheimer’s disease cases with Presenilin 1 mutation

Project description:Presenilin 1 (PSEN1) is the most frequently mutated gene in early-onset sporadic and familial Alzheimer’s disease (FAD). The PSEN1 complex displays gamma-secretase activity and promotes cleavage of the C99-terminal fragment of the Amyloid Precursor Protein (APP) into the A42 peptide. PSEN1 is also involved in vesicle transport across ER and mitochondria in so called mitochondria associated membranes. We generated induced pluripotent stem cells (iPSCs) from 5 controls and 5 FAD cases carrying the PSEN1 A246E and L286V mutations. Unexpectedly, global gene expression profile analysis of FAD iPSCs revealed profound perturbation of mitochondrial, Golgi apparatus and ER pathways. PSEN1, APP and Nicastrin were highly expressed in iPSCs and PSEN1 localized to membrane-bound organelles. FAD iPSCs grown slower and showed elevated cell death together with abnormally high A42 secretion. Mitochondrial reactive oxygen species (ROS) were elevated in FAD iPSCs and treatment with a ROS scavenger significantly improved cell death, proliferation, and DNA damage. However, it could not improve the severe ATP deficit. Inhibition of gamma-secretase activity further exacerbated the overall FAD iPSC phenotype. Cortical neurons produced from the differentiation of FAD iPSCs showed Alzheimer’s pathology and TGFb pathway hyper-activation. PSEN1-mutant iPSCs may serve as a new model to perform genome-wide genetic screens and to study FAD pathophysiology and PSEN1 cellular function.

2024-06-20 | GSE253337 | GEO

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