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Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons

ABSTRACT: Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons

PROVIDER: PRJNA738469 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14828244_1.fastq.gz	Fastqsanger.gz
	SRR14828244_2.fastq.gz	Fastqsanger.gz
	SRR14828245_1.fastq.gz	Fastqsanger.gz
	SRR14828245_2.fastq.gz	Fastqsanger.gz
	SRR14828246_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons

Project description:Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD+ homeostasis for health and function, the specific roles of subcellular NAD+ pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, large-scale transcriptomics reveals dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.

2021-06-17 | GSE178312 | GEO

NAD+ repletion inhibits accelerated aging in Werner syndrome through the restoration of mitophagy

Project description:Metabolic dysfunction is a primary feature of the premature aging Werner syndrome (WS), a heritable human disease caused by mutations in the gene encoding the DNA helicase Werner (WRN). However, the relationship between WRN mutation and its severe metabolic phenotypes is unclear. Here we report mitochondrial dysfunction and depletion of NAD+, a fundamental ubiquitous cofactor, in WS patient samples and WS animal models. NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably delays accelerated aging, including stem cell dysfunction in both C. elegans and Drosophila models of WS. Mechanistically, WRN physically binds to a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) and facilitates its NAD+ production. Our findings reveal an unprecedented anti-aging mechanism of WRN that integrates its new function of NAD+ synthesis to coordinate mitochondrial maintenance and energy expenditure, and suggest therapeutic potential.

2019-08-16 | GSE108968 | GEO

Adipocyte-specific inactivation of NAMPT, a key NAD+ biosynthetic enzyme, causes a metabolically-unhealthy lean phenotype in female mice during aging

Project description:Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole-body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤ 4-month-old), middle aged (10 to 14-month-old), and old (≥ 18-month-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic euglycemic clamp procedure demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPARγ) in an age-dependent manner. In addition, administration of a PPARγ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPARγ axis in maintaining functional integrity and quantity of adipose tissue, and whole-body metabolic function in female mice during aging.

2024-05-31 | GSE152067 | GEO

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Project description:Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

2020-01-13 | PXD015644 | Pride

Expression analysis upon NMNAT1 knockdown in MCF-7 cells

Project description:NMNAT1 is a nuclear enzyme in the mammalian NAD+ salvage pathway. Expression microarray analysis was used to study the effect of NMNAT1 knockdown on gene expression in MCF-7 breast cancer cells.

2009-05-28 | GSE13458 | GEO

Comprehensive gene expression profile of mouse explant retinas expressing shNmnat1, shNmnat2, Nmnat1 and Nmnat2

Project description:Nmnat1 and Nmnat2 are NAD synthases that localize to the nucleus and cytoplasm, respectively. They contribute to not only metabolic pathway but also the gene expression through the regulation of NAD-dependent enzymes. Both genes have been shown to be essential for normal retinal development, but the differences between these downstream factors are not well understood. In this study, we performed RNA-sequencing using mouse retinal explants transfected with control, Nmnat1-, Nmnat2-, shNmnat1-, shNmnat2-expressing plasmids. Mouse retinas at postnatal day 0.5 were electroporated with the plasmids and cultured for 3 days. EGFP-expressing cells were purified by a cell sorter, and RNA-seq was carried out.

2022-02-25 | GSE197192 | GEO

Adipocyte-specific inactivation of NAMPT, a key NAD+ biosynthetic enzyme, causes a metabolically-unhealthy lean phenotype in female mice during aging

Project description:Adipocyte-specific inactivation of NAMPT, a key NAD+ biosynthetic enzyme, causes a metabolically-unhealthy lean phenotype in female mice during aging

| PRJNA638180 | ENA

Transcriptomic effects of nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion on human AML cells

Project description:Through integration of whole genome CRISPR screening and pan-cancer genetic dependency mapping, we identified nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) as acute myeloid leukemia (AML) dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, we found that the presence of NAD+ precursors bypassed the dependence of AML on NAMPT, but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. We provide evidence that reduced nuclear NAD+ upon deletion of NMNAT1 activated p53, which is due to attenuated deacetylation by SIRT6/7 in AML cells. Our findings reveal that NAD+ is a critical metabolic foundation for AML, and NMNAT1 is a novel therapeutic target for this disease.

2021-07-28 | GSE171565 | GEO

Decapping enzyme NUDT12 partners with BLMH for cytoplasmic surveillance of NAD-capped RNAs

Project description:RNA polymerase II transcripts receive a protective 5ʹ m7G cap early during transcription. An alternative cap can be acquired when RNA pol II initiation uses the redox cofactor nicotinamide adenine dinucleotide (NAD) to generate NAD-capped RNAs. The biology of mammalian NAD-RNAs, including its turnover and physiological roles are not completely understood. Here we identify NUDT12 as a cytosolic decapping enzyme for NAD-RNAs. Structural, biochemical and functional studies reveal how homodimerization modulates specificity of NUDT12 for NAD-RNAs as substrate. NUDT12 is localized within a few discrete cytoplasmic granules that are distinct from P-bodies. We identity Bleomycin hydrolase (BLMH) as a factor that associates with NUDT12 in a large ~600 kDa dodecamer complex, and we demonstrate that BLMH is required for correct localization of NUDT12 into these granules. This complex is functional in human cell cultures, as artificial tethering of BLMH to a reporter mRNA results in downregulation of reporter expression, similar to that seen with tethering of NUDT12. Analysis of mouse liver transcriptome from the Nudt12 knockout mouse reveals that a select set of RNAs are regulated, including a significant upregulation of circadian clock transcripts. Given that NAD biosynthesis is under circadian control, our study points to a physiological role for the cytosolic surveillance of NAD-RNAs.

2019-12-25 | GSE138019 | GEO

Overexpression of human estrogen biosynthetic enzyme Hydroxysteroid (17beta) dehydrogenase type 1 which induces adenomyosis-like phenotype in transgenic mice

Project description:We report uterine mRNA transcriptome sequencing of mice over-expressing human estrogen biosynthetic enzyme HSD17B1 (HSD17B1TG mice) present with adenomyosis phenotype.

2022-05-17 | GSE199492 | GEO

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