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A small molecule modulator of prion protein enhances proliferation and engraftment of mesenchymal stem cells and extends their lifespan upon serial passage in culture

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Claire Cairney

PROVIDER: E-GEOD-31205 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A small molecule modulator of prion protein enhances proliferation and engraftment of mesenchymal stem cells and extends their lifespan upon serial passage in culture

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

Transcriptional signature of prion-induced neurotoxicity in a Drosophila model of transmissible mammalian prion disease

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

The prion protein interactome in four mouse cell lines of distinct lineages

Project description:At times, it can be difficult to discern if a lack of overlap in reported interactions for a protein-of-interest reflects differences in methodology or biology. A case in point is the prion protein (PrP) which is best known for its central role in prion disorders. Despite having over two dozen interactors reported, there is little consensus regarding their importance for understanding the biology of PrP. In such instances, systematic analyses of protein-protein networks across diverse paradigms can provide valuable insights. Here, we interrogated the PrP interactome in four distinct mouse cell lines. Analyses made use of identical affinity capture reagents and sample processing workflows. To enable the discrimination of specific from non-specific binders, negative controls were generated from PrP knockout lines of the respective cell models, and the relative levels of peptides were quantified with the help of isobaric labels. The study uncovered 26 proteins, which reside in proximity to PrP. All of these proteins are predicted to have access to the outer face of the plasma membrane, and approximately half of them were not reported to interact with PrP before. Strikingly, although several proteins exhibited profound co-enrichment with PrP in a given model, except for Ncam1, no protein was highly enriched in all four PrP-specific interactome datasets.

2018-05-24 | PXD008781 | Pride

The Prion Protein (PrP) is involved in translation via RNA granule-like mRNPs, a connection which is impaired during neurodegenerative diseases

Project description:Cytoplasmic RNA granules have emerged as important elements of posttranscriptional and translational regulation. Stress, germinal and neuronal granules contain RNA-binding proteins capable of self-assembly due to prion-like domains. Hyperassembly mediated by these prion-like domains causes several neurodegenerative diseases. Here, we report a subset of the mammalian prion protein (PrP), also prone to self-assembly, propagation and to cause devastating diseases, is a component of naturally occurring messenger ribonucleoproteins (mRNPs) in adult mouse brains. Biomolecules co-purified with PrP revealed a multitude of diverse RNA granule associated proteins and mRNAs encoding members of the translation machinery, indicating a role in a specialized translation process. Importantly, PrP mutations linked to Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI) severely impaired recovery of mRNPs from preclinical mice, possibly representing a very early pathological process. Thus, mutant PrP may cause dysfunction in RNA regulation, thereby joining the constantly expanding ranks of disease associated RNP granule proteins. The file Enrichment_analysis.xlsx contains mRNAs (FDR < 0.01) co-purified with PrP in both WT sample pools as identified by DESeq2 and the respective gene counts and log2 fold changes for CJD and FFI PrP:IP sample pools.

2015-11-01 | GSE57233 | GEO

The Prion Protein (PrP) is involved in translation via RNA granule-like mRNPs, a connection which is impaired during neurodegenerative diseases

2015-11-01 | E-GEOD-57233 | biostudies-arrayexpress

Brain-wide AAV-mediated silencing of prion protein by a compact epigenetic editor

Project description:Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid onset dementia and death. However, elimination of endogenous PrP can halt prion disease progression. Here, we describe CHARM, a compact, enzyme-free epigenetic editor capable of silencing transcription through programmable targeted DNA methylation. Using a histone H3 tail-Dnmt3l fusion, CHARM recruits and activates the endogenous DNA methyltransferases, thereby reducing transgene size and bystander effects. When delivered to the mouse brain by an adeno-associated viral (AAV) vector, PRNP-targeted CHARM ablates PrP expression across the brain. We temporally limit editor expression by implementing a kinetically-tuned self-silencing approach. CHARM represents a broadly applicable strategy to programmably prevent expression of pathogenic proteins, including those implicated in other neurodegenerative diseases.

2024-05-03 | GSE255987 | GEO

Interactomes of neural cell adhesion molecule 1 and the metal ion transporter ZIP6 in mouse NMuMG epithelial cells with transforming growth factor beta 1-induced fibroblastoid morphology

Project description:The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs 5, 6 and 10, raising the prospect that the study of these ZIPs may reveal insights relevant for understanding PrP function. PrP and ZIP6 are required for the execution of a cellular program known as epithelial-to-mesenchymal transition (EMT). Polysialylation of neural cell adhesion molecule 1 (NCAM1) during EMT is also controlled by PrP. Here we report the ZIP6 interactome and ZIP6-dependent NCAM1 interactome in a mouse cell EMT model.

2017-02-13 | PXD004685 | Pride

Transcription profiling of mouse brain infected with prions in eight mouse-prion strain combinations in a systems approach to the study of prion disease

Project description:Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal, benign forms of prion protein (PrPC) to disease-causing PrPSc isoforms. A systems approach to disease postulates that disease arises from the pathological perturbation (genetic and/or environmental) of one or more biological networks in the relevant organ. In this regard, we tracked global (all mRNA transcripts) gene expression in the brains of eight distinct mouse strain-prion strain combinations at 8 - 10 time points throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Data are also available from http://prion.systemsbiology.net

2009-03-25 | E-MTAB-76 | biostudies-arrayexpress

mouse brain prion protein interactome

Project description:In vertebrates, the prion protein (PrP, gene name Prnp) is expressed in diverse cell types and tissues, especially in the brain. In the adult brain, PrP contributes to homeostasis. Here, proteins expressed in the adult mouse brain which coimmunoprecipitated with PrP via the Fab antibody D18 were identified by comparison to PrP-specific immunoprecipitates from Prnp knockout brain.

2021-11-02 | PXD024870 | Pride

Gene expression profile at single cell level of CD8+ T cells and NK cells as part of neonatal antiviral response in C57BL/6J and PrP KO mice infected with mouse cytomegalovirus (MCMV)

Project description:Cytomegaloviral (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, we investigated the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. We used single cell RNA sequencing (scRNA-seq) to analyze the differences in CD8+ T cell and NK cell response to congenital MCMV infection in wild type mice and strain lacking functional PrP protein (PrP KO).

2024-07-22 | GSE245338 | GEO

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