A prion accelerates proliferation at the expense of lifespan
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA644577 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12163000.fastq.gz | Fastqsanger.gz | |||
| SRR12163001.fastq.gz | Fastqsanger.gz | |||
| SRR12162992.fastq.gz | Fastqsanger.gz | |||
| SRR12162993.fastq.gz | Fastqsanger.gz | |||
| SRR12162994.fastq.gz | Fastqsanger.gz |
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Project description:A prion accelerates proliferation at the expense of lifespan [samples with spike-in controls]
| PRJNA736730 | ENA
Project description:Organisms often commit to one of two strategies: living fast and dying young or living slow and dying old. In fluctuating environments, however, switching between these two strategies could be advantageous. Lifespan is often inversely correlated with cell size and proliferation, which are both limited by protein synthesis. Here we report that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion can grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential expression of hundreds of proteins, including many that regulate proliferation and aging. Our data reveal a functional role for aggregation of RNA-modifying enzymes in driving heritable epigenetic states that transform cell growth and survival.
2020-07-08 | GSE153930 | GEO
Project description:Manuscript abstract: In fluctuating environments, the ability to switch between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Tradeoffs arise, however. Mechanisms that aberrantly increase cell size or proliferation— such as mutations, or chemicals that interfere with growth regulatory pathways—can also shorten lifespan. Here we report a natural example of how the interplay between growth and lifespan can be epigenetically controlled. We find that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential synthesis of dozens of proteins, including many that regulate proliferation and aging. Our data reveal a new role for prion-based control of an RNA-modifying enzyme in driving heritable epigenetic states that transform cell growth and survival.
2021-06-11 | GSE176577 | GEO
Project description:In fluctuating environments, switching between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Trade-offs arise, however. Mechanisms that aberrantly increase cell size or proliferation-such as mutations or chemicals that interfere with growth regulatory pathways-can also shorten lifespan. Here we report a natural example of how the interplay between growth and lifespan can be epigenetically controlled. We find that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential synthesis of dozens of proteins, including many that regulate proliferation and aging. Our data reveal a new role for prion-based control of an RNA-modifying enzyme in driving heritable epigenetic states that transform cell growth and survival.
| S-EPMC8455135 | biostudies-literature
Project description:Human mesenchymal stem cells (hMSC) play an important role in the maintenance of bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSC lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Here we show that targeting prion protein (PrP) by chemical intervention delays this process. When PrP expression was knocked down, cultures showed significant reduction in proliferation and differentiation capacity. In contrast hMSC expanded in the presence of small molecule modulator of PrP expression, 3/689, showed extended lifespan up to 10 population doublings. Upon re-plating cultures contained more than double the number of clonogenic progenitors and showed a 10 fold increase in engraftment levels in bone marrow 5 weeks post-transplant. Human MSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression. Gene expression profiling revealed upregulation of superoxide dismutase 2 in cells treated with 3/689, dependent on PrP expression, and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target to delay loss of proliferation and differentiation of hMSC with expansion in culture. Gene expression changes in hMSC expanded in the presence of 10uM small molecule modulator of prion protein 3/689 or DMSO were analysed at passage 2 and passage 8 from 3 separate donors.
2012-01-30 | E-GEOD-31205 | biostudies-arrayexpress
Project description:Human mesenchymal stem cells (hMSC) play an important role in the maintenance of bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSC lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Here we show that targeting prion protein (PrP) by chemical intervention delays this process. When PrP expression was knocked down, cultures showed significant reduction in proliferation and differentiation capacity. In contrast hMSC expanded in the presence of small molecule modulator of PrP expression, 3/689, showed extended lifespan up to 10 population doublings. Upon re-plating cultures contained more than double the number of clonogenic progenitors and showed a 10 fold increase in engraftment levels in bone marrow 5 weeks post-transplant. Human MSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression. Gene expression profiling revealed upregulation of superoxide dismutase 2 in cells treated with 3/689, dependent on PrP expression, and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target to delay loss of proliferation and differentiation of hMSC with expansion in culture.
2012-01-30 | GSE31205 | GEO
Project description:Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice
| PRJNA596388 | ENA
Project description:Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly-treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.
2020-01-31 | GSE144028 | GEO
Project description:Prions consist of aggregates of abnormal conformers of cellular prion protein (PrPC). They propagate by recruiting host-encoded PrPC although the critical interacting proteins and the reasons for the differences in susceptibility of distinct cell lines and populations are unknown. We derived a lineage of cell lines with markedly differing susceptibilities, unexplained by PrPC expression differences, to identify such factors. We examined the transcriptomes of prion-resistant revertants, isolated from highly susceptible cells, and identified a gene expression signature associated with susceptibility. Several of these genes encode proteins with a role in extracellular matrix (ECM) remodelling, a compartment in which disease-related PrP deposits. Loss-of-function of nine of these genes significantly increased susceptibility. Remarkably, inhibition of fibronectin 1 binding to integrin α8 by RGD peptide inhibited metalloproteinases (MMP)-2/9 whilst increasing prion propagation rates. This indicates that prion replication may be controlled by MMPs at the ECM in an integrin-dependent manner.
2014-07-31 | GSE56275 | GEO
Project description:This report describes our study of the efficacy and the potential mechanism underlying the anti-prion action of a new anti-prion compound having a glycoside structure in prion-infected cells. The study revealed involvements of two factors in the mechanism of the compound action: interferon and a microtubule nucleation activator, phosphodiesterase 4D interacting protein. In particular, phosphodiesterase 4D interacting protein was suggested to be important in regulating the trafficking or fusion of prion protein-containing vesicles or structures in cells. The findings of the study are expected to be useful not only for the elucidation of cellular regulatory mechanisms of prion protein, but also for the implication of new targets for therapeutic development. Prion-infected N167 cells were treated with either anti-prion glycoside compound (Gly-9) or control glycoside compound (Gly-14) at a dose of 5 M-NM-<g/mL for three days. Then, gene expression profiles were analyzed by DNA microarray analysis. Experiments were performed in quadruplicate.
2014-02-22 | E-GEOD-55241 | biostudies-arrayexpress