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The NAD + Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC, iPSC derived Neural Stem Cells and cortical Organoid of Alpers’ Disease

ABSTRACT: To investigate the transcriptomic profile and molecular machnisiums using RNA sequecning analysis for the iPSC derived neural cells and brain organoids from the patient of Alpers’ Disease We then performed gene expression profiling analysis using data obtained from RNA-seq of the iPSC derived neural cells and brain organoids from the patient of Alpers’ Disease and healthy controls

ORGANISM(S): Homo sapiens

PROVIDER: GSE225718 | GEO | 2023/02/24

REPOSITORIES: GEO

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The NAD + Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC, iPSC derived Neural Stem Cells and cortical Organoid of Alpers’ Disease

Project description:The NAD + Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC, iPSC derived Neural Stem Cells and cortical Organoid of Alpers’ Disease

| PRJNA937223 | ENA

Nicotinamide Riboside and Dihydronicotinic Acid Riboside Synergistically Increase Intracellular NAD<sup>+</sup> by Generating Dihydronicotinamide Riboside.

Project description:Through evolution, eukaryote organisms have developed the ability to use different molecules as independent precursors to generate nicotinamide adenine dinucleotide (NAD+), an essential molecule for life. However, whether these different precursors act in an additive or complementary manner is not truly well understood. Here, we have evaluated how combinations of different NAD+ precursors influence intracellular NAD+ levels. We identified dihydronicotinic acid riboside (NARH) as a new NAD+ precursor in hepatic cells. Second, we demonstrate how NARH, but not any other NAD+ precursor, can act synergistically with nicotinamide riboside (NR) to increase NAD+ levels in cultured cells and in mice. Finally, we demonstrate that the large increase in NAD+ prompted by the combination of these two precursors is due to their chemical interaction and conversion to dihydronicotinamide riboside (NRH). Altogether, this work demonstrates for the first time that NARH can act as a NAD+ precursor in mammalian cells and how different NAD+ precursors can interact and influence each other when co-administered.

| S-EPMC9269339 | biostudies-literature

Nicotinamide riboside kinase structures reveal new pathways to NAD+.

Project description:The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+) by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+.

| S-EPMC1994991 | biostudies-literature

Proteomic signatures of schizophrenia-sourced iPSC-derived brain organoids

Project description:Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease. Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors, early neurons, and brain organoids. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis. Multiple dysregulated proteins were found in pathways related to synapses, in line with postmortem tissue studies of schizophrenia patients. However, organoids and immature neurons exhibit impairments in pathways never before found in patient-derived induced pluripotent stem cell studies, such as spliceosomes and amino acid metabolism. In conclusion, here we provide comprehensive, large-scale, protein-level data that may uncover underlying mechanisms of the developmental origins of schizophrenia.

2023-03-11 | PXD026381 | Pride

Proteomic signatures of schizophrenia-sourced iPSC-derived neural progenitors and neurons

2023-03-11 | PXD026593 | Pride

Nicotinamide Riboside Is a Major NAD+ Precursor Vitamin in Cow Milk.

Project description:BackgroundNicotinamide riboside (NR) is a recently discovered NAD(+) precursor vitamin with a unique biosynthetic pathway. Although the presence of NR in cow milk has been known for more than a decade, the concentration of NR with respect to the other NAD(+) precursors was unknown.ObjectiveWe aimed to determine NAD(+) precursor vitamin concentration in raw samples of milk from individual cows and from commercially available cow milk.MethodsLC tandem mass spectrometry and isotope dilution technologies were used to quantify NAD(+) precursor vitamin concentration and to measure NR stability in raw and commercial milk. Nuclear magnetic resonance (NMR) spectroscopy was used to test for NR binding to substances in milk.ResultsCow milk typically contained ∼12 μmol NAD(+) precursor vitamins/L, of which 60% was present as nicotinamide and 40% was present as NR. Nicotinic acid and other NAD(+) metabolites were below the limits of detection. Milk from samples testing positive for Staphylococcus aureus contained lower concentrations of NR (Spearman ρ = -0.58, P = 0.014), and NR was degraded by S. aureus Conventional milk contained more NR than milk sold as organic. Nonetheless, NR was stable in organic milk and exhibited an NMR spectrum consistent with association with a protein fraction in skim milk.ConclusionsNR is a major NAD(+) precursor vitamin in cow milk. Control of S. aureus may be important to preserve the NAD(+) precursor vitamin concentration of milk.

| S-EPMC6879052 | biostudies-literature

RNA-seq of retinal organoids derived from RPGR patient-, control- and mutation-corrected-iPSC at different developmental stages

Project description:Retinitis pigmentosa (RP) is an irreversible and inherited retinopathy. RPGR mutations are the most common causes of this disease. It remains challenging to decipher the mechanism of RPGR mutation because of the lack of appropriate study models. The substitution of patient-specific diseased retina without ethical restrictions is desired and iPSC-derived 3D retina is the best choice. In our experiment, we generated iPSCs from one RP patient with 2-bp frameshift mutation in the exon14 of RPGR gene, which were differentiated into retinal organoids. Also we generated iPSCs from a normal control and differentiated those control-iPSCs into healthy retinal organoids. Samples of patient- and control-retinal organoids at W0, W7, W13 (two replicates), W18 (two replicates) and W22 (two replicates for patient) were collected for RNA-seq. Corrected-iPSC were derived from CRISPR/Cas9-mediated gene correction. Then we collected the corrected-iPSC derived retinal organoids at W0, W7, W13 (two replicates), W18 (two replicates) and W22 (two replicates) for RNA-seq. Through the RNA-seq data, we demonstrate that patient-specific iPSC-dervied 3D retinae can recapitulate disease progress of Retinitis Pigmentosa through presenting defects in photoreceptors' gene profile. CRISPR/Cas9-mediated gene correction can rescue photoreceptor gene profile. Those transcriptome are consistent with the phenotype and function.

2020-02-01 | E-MTAB-6490 | biostudies-arrayexpress

Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype

Project description:Purpose: A proof of concept study examining the disease modelling capabilities of patient iPSC derived kidney organoids. Methods: A proband was diagnosed by genome sequencing with compound heterozygous IFT140 mutations. A one-step reprogramming/gene-editing protocol of proband fibroblasts was used to derive both uncorrected patient and isogenic gene-corrected induced pluripotent stem cells (iPSC) which were differentiated to kidney organoids. Organoids were examined by immunofluorescence. Additionally, epithelial cells magnetically sorted from whole kidney organoids underwent transcriptional profiling and spheroid culture. Results: Differential expression analysis of organoid epithelial cell fractions demonstrated apicobasal polarity, cell-cell junction and dynein motor assembly downregulation in patient organoids. Defective ciliary morphology and spheroid culture were rescued in gene corrected organoids. Conclusions: This study validates patient iPSC-derived kidney organoids as a novel, faithful and patient-specific model to further the study of inherited renal disease in regenerated, human, in vitro tissue.

2018-04-26 | GSE107230 | GEO

snRNA-Seq data of human iPSC-midbrain organoids without and with microglia

Project description:The human brain is a complex, three-dimensional structure. To better recapitulate the brain complexity, recent efforts focused on the development of human specific midbrain organoids. Midbrain organoids consist of differentiated and functional neurons, which contain active synapses, as well as astroglia and oligodendrocytes. However, the absence of microglia, with their ability to phagocyte apoptotic cells and debris represents a major disadvantage for the midbrain organoid system. Additionally, neuro-inflammation-related disease modeling is not possible in the absence of microglia. So far, no studies about the effects of iPSC-derived microglia in brain organoid neural cells have been published. Here we describe an approach to derive microglia from human iPSCs and integrate them into midbrain organoids. Using single nuclear RNA sequencing in collaboration with the RIKEN institute we provide a detailed characterization of the microglia in brain organoids as well as of the influence their presence has on the other cells of the organoids.

2022-09-18 | GSE213288 | GEO

Bulk RNA-seq of MilliporeSigma SCC300 human iPSC-derived colon organoids compared with undifferentiated human iPSCs and MilliporeSigma SCC321 human patient-derived colon organoids

Project description:Experiment intended to obtain expression profiles of iPSC-derived human colon organoids compared to undifferentiated human iPSCs and a patient-derived colon organoid line

2021-10-25 | E-MTAB-11026 | biostudies-arrayexpress

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