Efficacy and molecular mechanism of a glycoside compound inhibiting abnormal prion protein formation in prion-infected cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE55241 | GEO | 2014/02/22
SECONDARY ACCESSION(S): PRJNA238984
REPOSITORIES: GEO
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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
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: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 are self-propagating protein aggregates that act as protein-based genetic elements in fungi. Although prevalent in eukaryotes, prions have not been identified in bacteria. Here we demonstrate that a bacterial protein, transcription terminator Rho of Clostridium botulinum (Cb-Rho), can form a prion. Specifically, we identify a candidate prion-forming domain (cPrD) in Cb-Rho and show that it confers amyloidogenicity on Cb-Rho and can functionally replace the PrD of a yeast prion-forming protein. Furthermore, we show that its cPrD enables Cb-Rho to access alternative conformations in bacteria, a soluble form that terminates transcription efficiently and an aggregated, self-propagating prion form that is functionally compromised, causing genome-wide changes in the transcriptome. Thus, Cb-Rho functions as a protein-based genetic element in bacteria, suggesting that the emergence of prions predates the evolutionary split between eukaryotes and bacteria.
2017-02-13 | GSE90485 | GEO
Project description:Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death. The pathological effects of prion diseases in the brain are morphologically well defined, such as gliosis, vacuolation, and the accumulation of disease-specific protease-resistant prion protein (PrPSc). However, the underlying molecular events that lead to the death of neurons are poorly characterised. In this study cDNA microarrays were used to profile gene expression changes in the brains of two different strains of mice infected with three strains of mouse-adapted scrapie. Extensive data was collected and analyzed, from which we identified a core group of 349 prion-related genes (PRGs) that consistently showed altered expression in mouse models. Gene ontology analysis assigned many of the up-regulated genes to functional groups associated with one of the primary neuropathological features of prion diseases, astrocytosis and gliosis; protein synthesis, inflammation, cell proliferation and lipid metabolism. Using a computational tool, Ingenuity Pathway Analysis (IPA), we were able to build networks of interacting genes from the PRG list. The regulatory cytokine TGFB1, involved in modulating the inflammatory response, was identified as the outstanding interaction partner for many of the PRGs. The majority of genes expressed in neurons were down-regulated; a number of these were involved in regulatory pathways including synapse function, calcium signalling, long-term potentiation and ERK/MAPK signalling. Two down-regulated genes coding for the transcription regulators, EGR1 and CREB1, were also identified as central to interacting networks of genes; these factors are often used as markers of neuronal activity and their deregulation could be key to loss of neuronal function. These data provides a comprehensive list of genes that are consistently differentially expressed in multiple scrapie infected mouse models. Building networks of interactions between these genes provides a means to understand the complex interplay in the brain during neurodegeneration. Resolving the key regulatory and signaling events that underlie prion pathogenesis will provide targets for the design of novel therapies and the elucidation of biomarkers. Keywords: disease state analysis
2008-01-31 | GSE10310 | GEO
Project description:MicroRNA alterations were investigated in a Tg501 mouse model of prion disases that express the goat prion protein (PRNP). Age-matched Tg501 mice without inoculation (controls) and intracranially inoculated with caprine scrapie strain were compared in presymptomatic and symptomatic stages.
2020-06-17 | GSE146013 | GEO
Project description:Sheep scrapie (Sc) is the classical transmissible spongiform encephalopathy (prion disease). The conversion of normal cellular prion protein (PrPC) to disease-associated prion protein (PrPSc) is a fundamental component of prion disease pathogenesis. The molecular mechanisms contributing to prion diseases and the impact of PrPSc accumulation on cellular biology are not fully understood. To define the molecular changes associated with PrPSc accumulation, primary sheep microglia were inoculated with PrPSc and then the transcriptional profile of these PrPSc-accumulating microglial cells was compared to the profile of PrPSc-lacking microglial cells using the Affymetrix Bovine Genome Array. The experimental design included three biological replicates, each with three technical replicates, and samples that were collected at the point of maximal PrPSc accumulation levels as measured by ELISA. The array analysis revealed 19 upregulated genes and 30 downregulated genes in PrPSc-accumulating microglia. Three transcripts (CCL2, SGK1, and AASDHPPT) were differentially regulated in a direction similar to previous reports from mouse or human models, whereas the response of three other transcripts (MT1E, NR4A1, PKP2) conflicted with previous reports. Overall, the results demonstrated a limited transcriptional response to PrPSc accumulation, when compared to microglia and macrophage cultures infected with other agents such as viruses and bacteria. This is the first microarray-based analysis of prion accumulation in primary cells derived from a natural TSE-host. Keywords: disease state analysis
2008-09-06 | GSE12688 | GEO
Project description:Dr. Wong's laboratory is interested in examining if and how the absence of prion protein expression could affect the cellular glycosylation enzymes during development. Prion protein is a glycoprotein and changes in glycosylation on the protein have been implicated in the pathogenic process. Our objective is to examine if and how the absence of prion protein expression could affect the cellular glycosylation enzymes during development. To do this, we proposed to compare and contrast the expression profile of the glycosylation enzymes in control and prion protein knockout mouse brain at the age of 2 and 82 weeks (n=3). RNA preparations from control and prion protein knockout mice brain of age ~2 and 82 weeks were sent to the Microarray Core (E). The RNA was amplified, labeled, and hybridized to GLYCOv3 microarrays.
2011-04-29 | E-GEOD-28935 | biostudies-arrayexpress
Project description:The neuroblastoma-derived cell line N2a is permissive to certain prion strains but resistant sublines unable to accumulate the pathological proteinase-K resistant form of the prion protein can be isolated. We compared for gene expression and phenotypes different N2a sublines that were susceptible or resistant to the 22L prion strain. Karyotypes and comparative genomic hybridization arrays revealed chromosomal imbalances but did not demonstrate a characteristic profile of genomic alterations linked to prion susceptibility. Likewise, we showed that this phenotype was not dependent on the binding of PrPres, the expression of the prion protein gene, or on its primary sequence. We completed this analysis by looking using real-time quantitative PCR at the expression of a set of genes encoding proteins linked to prion biology. None of the candidates could account by itself for the infection phenotype, nevertheless sublines had distinct transcriptional profiles. Taken together, our results do not support a role for specific genomic abnormalities and possible candidate proteins in N2a prion susceptibility. They also reveal genetic heterogeneity among the sublines and serve as a guidance for further investigation into the molecular mechanisms of prion infection.
2008-09-08 | GSE5374 | GEO
Project description:Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
2023-01-31 | GSE214375 | GEO