Klotho inhibits neuronal senescence in human brain organoids
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ABSTRACT:
PROVIDER: PRJNA720649 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14183937_1.fastq.gz | Fastqsanger.gz | |||
| SRR14183937_2.fastq.gz | Fastqsanger.gz | |||
| SRR14183938_1.fastq.gz | Fastqsanger.gz | |||
| SRR14183938_2.fastq.gz | Fastqsanger.gz | |||
| SRR14183939_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:We report the application of brain organoids to study cellular senescence, in particular Klotho declining in expresssion mediates neuronal senescence, bulk RNA-sequencing further identified the potenital downstream target tha may modulate cellular senescence in the brain.
2021-04-09 | GSE171719 | GEO
Project description:Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.
| S-EPMC8329278 | biostudies-literature
Project description:Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknow. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons as a metabolic substrate contributing to fulfill their elevated energy requirements.
2018-03-08 | GSE100046 | GEO
Project description:ZNF281 inhibits neuronal differentiation
| PRJNA438998 | ENA
Project description:α-Klotho has emerged as a powerful regulator of the ageing process. To-date, the expression profile of α-Klotho in human tissues is unknown and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize system-wide tissue expression of transmembrane α-Klotho in humans. We have employed next generation targeted proteomic analysis using Parallel Reaction Monitoring (PRM) in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health. Results: The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive and neuronal tissues was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, while liver did not reveal a detectable signal. These results were next confirmed by western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho expressing tissues were subjected to PRM mass spectrometry identifying peptides specific for the full length, transmembrane α-Klotho isoform. Conclusions: The data presented confirms α-Klotho expression in the kidney tubule and in artery, and provides evidence of α-Klotho expression across organ systems and cell-types that have not previously been described in humans.
2015-10-13 | PXD002775 | Pride
Project description:?-Klotho has emerged as a powerful regulator of the ageing process. To-date, the expression profile of ?-Klotho in human tissues is unknown and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize system-wide tissue expression of transmembrane ?-Klotho in humans. We have employed next generation targeted proteomic analysis using Parallel Reaction Monitoring (PRM) in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human ?-Klotho expression in health. Results: The distribution of ?-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive and neuronal tissues was first identified by immunohistochemistry. Kidney tissues showed strong ?-Klotho expression, while liver did not reveal a detectable signal. These results were next confirmed by western blotting of both whole tissues and primary cells. To validate our antibody-based results, ?-Klotho expressing tissues were subjected to PRM mass spectrometry identifying peptides specific for the full length, transmembrane ?-Klotho isoform. Conclusions: The data presented confirms ?-Klotho expression in the kidney tubule and in artery, and provides evidence of ?-Klotho expression across organ systems and cell-types that have not previously been described in humans.
2017-03-29 | MSV000080719 | MassIVE
Project description:The expression profiles of miRNAs in klotho-deficient and wild-type mice were examined by means of GenopalM-BM-.-MICM DNA chips. The data suggested that there was a difference in the expression of miRNAs between klotho-deficient and wild-type mice. Small RNA samples prevared from 5-week-old klotho-deficient and wild-type mice were examined.
2012-11-01 | E-GEOD-34531 | biostudies-arrayexpress
Project description:Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here we examined the effects of Klotho on MO3.13, a human oligodendroglioma cell line in order to determine the potential role of Klotho as a tumor suppressor. We show that exogenous Klotho affects the ERK and Akt signaling pathways and decreases the proliferative abilities of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80% of the differentially expressed genes being downregulated. Using gene set enrichment analysis we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain malignancies. 6 Samples
2014-06-09 | E-GEOD-51536 | biostudies-arrayexpress
Project description:Brain organoids are promising tools for disease modelling and drug development. For proper neuronal network formation excitatory and inhibitory neurons as well as glia need to co-develop. Here we report the directed differentiation and self-organization of induced pluripotent stem cells in a collagen hydrogel towards a highly interconnected neuronal network in a macroscale tissue format. Bioengineered Neuronal Organoids (BENOs) comprise interconnected excitatory and inhibitory neurons as well as supportive astrocytes and oligodendrocytes. Giant depolarizing potential (GDP)-like events observed within 20-40 days of BENO culture mimic early network activity of the fetal brain. The switch from excitatory to inhibitory GABA activity, and reduced GDPs at >40 day BENO cultures indicate progressive neuronal network maturation. BENOs demonstrate expedited complex network burst development after two months of culture and provide the first evidence for long-term potentiation and plasticity in brain organoids. BENOs exhibit structural and functional properties similar to the fetal brain and thus may be explored as a model to study the development of neuronal plasticity.
2020-07-02 | GSE139101 | GEO
Project description:Study the role of klotho as a tumor suppressor in colorectal cancer. [abstract] Klotho is an anti-aging transmembrane protein, which can be shed and function as a hormone. Accumulating data indicate klotho as a tumor suppressor in a wide array of malignancies and indicate the subdomain KL1 as the active region of the protein. We aimed to study the role of klotho as a tumor suppressor in colorectal cancer. Bioinformatics analyses of TCGA datasets indicated reduced klotho mRNA levels in human colorectal cancer, along with negative regulation of klotho expression by hypermethylation of the promoter and 1st exon, and hypomethylation of an area within the gene. Overexpression or treatment with klotho or KL1 inhibited proliferation of colorectal cancer cells in vitro. The in vivo activity of klotho and KL1 was examined using two models recapitulating development of tumors in the normal colonic environment of immune-competent mice. Treatment with klotho inhibited formation of colon polyps induced by the carcinogen azoxymethane, and KL1 treatment slowed growth of orthotopically-implanted colorectal tumors. Gene expression array revealed that klotho and KL1 expression enhanced the unfolded protein response (UPR) and this was further established by increased levels of spliced XBP1, GRP78 and phosphorylated eIF2α. Furthermore, attenuation of the UPR partially abrogated klotho tumor suppressor activity. In conclusion, this study indicates klotho as a tumor suppressor in colorectal cancer and identifies, for the first time, the UPR as a pathway mediating klotho activities in cancer. These data suggest that administration of exogenous klotho or KL1 may serve as a novel strategy for prevention and treatment of colorectal cancer.
2018-08-09 | GSE118278 | GEO