Dysregulated microRNAs in blood correlate with central nervous system neuropathology of prion disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1214347 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The role of microRNAs (miRNAs) in neurodegenerative diseases has gained significant attention due to their involvement in gene regulation and potential as biomarkers. In prion diseases, including scrapie, miRNAs may modulate pathogenesis and disease progression. This study investigated circulating miRNA profiles in blood of sheep naturally affected by scrapie at preclinical and clinical stages using small RNA sequencing and RT-qPCR validation. While only one novel miRNA was dysregulated in preclinical blood samples, 66 previously identified miRNAs were significantly dysregulated in clinical sheep compared to healthy ones. These miRNAs were associated with pathways commonly altered in neurodegenerative diseases, such as autophagy, ubiquitin-mediated proteolysis, and endoplasmic reticulum protein processing. Notably, miR-1271-5p, let-7f-5p, miR-186-5p, and miR-425-5p showed consistent upregulation in the central nervous system of clinical animals, replicating the results observed in blood, with an increasing trend already in the preclinical stage and a strong correlation with neuropathological prion features. Additionally, predicted target genes such as UBQLN2, PGK1, KRAS, and CLTC were inversely expressed relative to these miRNAs, supporting their regulatory roles. These findings highlight the relevance of circulating miRNAs in prion neuropathology and support further research into the specific functional roles of these miRNAs and their predictive capacity for disease progression.
2025-07-04 | GSE287730 | GEO
Project description:Scrapie is a Transmissible Spongiform Encephalopathy (TSE) that affects sheep and goats and it is considered a good natural animal model to study prion diseases. Although changes in DNA methylation occur in many neurodegenerative diseases including human prion diseases, potential DNA methylation alterations have not yet been investigated in the central nervous system (CNS) of any prion disease models or naturally infected cases. We present here a whole genome bisulfite sequencing analysis (WGBS) from thalamus of four naturally scrapie infected sheep and four controls. All animals were female, carried the ARQ/ARQ genotype for the PRNP allele and were sacrificed at similar age (4 to 6 years old). Even if genomes displayed similar average methylation levels, we identified 39 differentially methylated promoters (DMP) and a total of 8,907 differentially methylated regions (DMR). Gene Ontology enrichment revealed that hypomethylated DMRs were enriched in genes involved in transmembrane transport and cell adhesion whereas hypermethylated DMRs were related with intracellular signal transduction genes. Moreover, we compared the set of identified DMRs with genes previously described to be differentially expressed in scrapie and with a set of genes encoding proteins defined to be tenfold more abundant in specific types of CNS cells finding that some of these genes also harboured DMRs. Finally, a validation study using qPCR was conducted showing differences in the expression of five genes (PCDH19, SNCG, WDR45B, PEX1 and CABIN1) that matched the methylation changes observed in the genomic study. Altogether, these findings suggest a potential regulatory role of CNS DNA methylation in prion diseases.
2022-03-10 | GSE184767 | 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:Detection of genome-wide methylation changes in prion-infected central nervous system
| PRJNA766085 | ENA
Project description:Neuronal hyperexcitability precedes synapse loss in certain neurodegenerative diseases, yet the synaptic membrane interactions and downstream signaling events remain unclear. The disordered amino terminus of the prion protein (PrPC) has been implicated in aberrant signaling in prion and Alzheimer’s disease. To disrupt neuronal interactions and signaling linked to the amino terminus, we CRISPR-engineered a knockin mouse expressing mutant PrPC (G92N), generating an N-linked glycosylation site between 2 functional motifs. Mice developed seizures and necrosis of hippocampal pyramidal neurons, similar to prion-infected mice and consistent with excitotoxicity. Phosphoproteomics analysis revealed phosphorylated
glutamate receptors and calcium-sensitive kinases, including protein kinase C (PKC). Additionally, 92N-PrPC-expressing neurons showed persistent calcium influx as well as dendritic beading, which was rescued by an N-methyl-d-aspartate receptor (NMDAR) antagonist. Finally, survival of Prnp92N mice was prolonged by blocking active NMDAR channels. We propose that dysregulated PrPC/NMDAR-induced signaling can trigger an excitatory, inhibitory imbalance, spongiform degeneration, and neurotoxicity and that calcium dysregulation is central to PrPC-linked neurodegeneration.
2024-03-28 | MSV000094427 | MassIVE
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
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.
2014-02-22 | GSE55241 | GEO
Project description:A comparison of prion infected and non-infected samples from neuroblastoma cells (N2a), and a comparison of prion infected and non-infected samples from hypothalmus cells (GT1). 11 dual-color DNA-chip hybridizations of cDNAs were made. Keywords: other
2005-08-24 | GSE1803 | GEO
Project description:A comparison of prion infected and non-infected samples from neuroblastoma cells (N2a), and a comparison of prion infected and non-infected samples from hypothalmus cells (GT1). 11 dual-color DNA-chip hybridizations of cDNAs were made. Keywords: other
2010-06-09 | E-GEOD-1803 | biostudies-arrayexpress