PrPC-facilitated cell signaling activates phospholipase Cɣ1 and triggers an Arc/Arg3.1 response in mouse neurons and human iPSC-derived neurons
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE327330 | GEO | 2026/04/13
REPOSITORIES: GEO
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Project description:Synapse dysfunction and synaptic loss are a central feature of neurodegenerative disorders, including prion disease. The cellular prion protein (PrPC) binds prion, amyloid-β, tau, and α-synuclein oligomers, resulting in the activation of macromolecular complexes and signaling at the post-synapse, yet the initial signaling events are unclear. Here we used a transcriptomic approach focused on the early-stage, prion-infected hippocampus of male wild type mice, and identify immediate early genes, including the synaptic activity response gene, Arc/Arg3.1, as significantly upregulated. In a longitudinal study of the prion-infected hippocampus, Arc/Arg-3.1 protein increased, from early to terminal disease. Notably, metabotropic glutamate receptor levels (mGluR5 dimers) were markedly reduced over time, while phosphorylated AMPA receptors (pGluA1-S845) levels increased. Sporadic Creutzfeldt-Jakob disease (sCJD) post-mortem cortical samples also showed low levels of mGluR5 dimers. Together, these findings suggest that prions trigger a chronic Arc response, an increase in phosphorylated GluA1, and a reduction in mGluR5 receptors beginning in early disease.
2023-01-01 | GSE207251 | GEO
Project description:A key event in the pathogenic process of prion diseases is the conversion of the cellular prion protein (PrPC) to an abnormal and protease-resistant isoform (PrPSc). Mice lacking PrP are resistant to prion infection, and down-regulation of PrPC during prion infection prevents neuronal loss and the progression to clinical disease. These results are suggestive of the potential beneficial effect of silencing PrPC during prion diseases. However, the silencing of a protein that is widely expressed throughout the CNS could be detrimental to brain homeostasis. The physiological role of PrPC remains still unclear, but several putative functions have been proposed. Among these, several lines of evidence support PrPC function in neuronal development and maintenance. To assess the influence of PrPC on gene expression profile during development in the mouse brain, we undertook a microarray analysis by using RNA isolated from the hippocampus, at two different developmental stages: newborn (4-day-old) and adult (3-month-old) mice, both from Prnp+/+ and Prnp0/0 animals. The comparison of the different datasets allowed us to identify “commonly” co-regulated genes and “uniquely” de-regulated genes during postnatal development in these animal models. The lack of PrPC during neuronal development affected several biological pathways, among which the most representative were cell signaling, cell-cell communication and transduction process. In addition, the absence of PrPC influenced genes involved in calcium homeostasis, nervous system development, synaptic transmission and cell adhesion. There was only a moderate alteration of the gene expression profile during neuronal development in the animal models we studied. PrPC deficiency does not lead to a dramatic alteration of gene expression profile, and produces moderate altered gene expression levels from young to adult animals. Thus, our results may provide additional support to silencing endogenous PrPC levels as a therapeutic approach to prion diseases.
2011-04-12 | GSE21718 | GEO
Project description:A key event in the pathogenic process of prion diseases is the conversion of the cellular prion protein (PrPC) to an abnormal and protease-resistant isoform (PrPSc). Mice lacking PrP are resistant to prion infection, and down-regulation of PrPC during prion infection prevents neuronal loss and the progression to clinical disease. These results are suggestive of the potential beneficial effect of silencing PrPC during prion diseases. However, the silencing of a protein that is widely expressed throughout the CNS could be detrimental to brain homeostasis. The physiological role of PrPC remains still unclear, but several putative functions have been proposed. Among these, several lines of evidence support PrPC function in neuronal development and maintenance. To assess the influence of PrPC on gene expression profile during development in the mouse brain, we undertook a microarray analysis by using RNA isolated from the hippocampus, at two different developmental stages: newborn (4-day-old) and adult (3-month-old) mice, both from Prnp+/+ and Prnp0/0 animals. The comparison of the different datasets allowed us to identify “commonly” co-regulated genes and “uniquely” de-regulated genes during postnatal development in these animal models. The lack of PrPC during neuronal development affected several biological pathways, among which the most representative were cell signaling, cell-cell communication and transduction process. In addition, the absence of PrPC influenced genes involved in calcium homeostasis, nervous system development, synaptic transmission and cell adhesion. There was only a moderate alteration of the gene expression profile during neuronal development in the animal models we studied. PrPC deficiency does not lead to a dramatic alteration of gene expression profile, and produces moderate altered gene expression levels from young to adult animals. Thus, our results may provide additional support to silencing endogenous PrPC levels as a therapeutic approach to prion diseases. To analyze the influence of PrPC expression on CNS gene expression profile during development, we investigated WT PrPC (Prnp+/+) and Prnp0/0 mice at two different developmental stages: in neonatal animals (postnatal day 4, P4) and in adult animals (3 months old). For each developmental stage, hippocampi of 3 (pups) or 4 (adult) animals were dissected immediately after animal sacrifice and promptly processed for RNA extraction and purification, for a total of 14 samples.
2011-04-12 | E-GEOD-21718 | biostudies-arrayexpress
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:An essential and remarkable process of the biochemical and physiological features in prion diseases is the conversion of a host-encoded prion protein (PrPC) into a misfolded isoform (PrPSc). The conversion of PrPC and the replication of prions, in cases of peripheral infection, occur following the uptake and subsequent spread of prions to brain via spinal cord. We investigated the changes of gene expression profiles in the spleen, cervical spinal cord and thalamus following intraperitoneal inoculation of ME7 scrapie prion and the inter-tissue alterations of the differentially expressed genes through Venn diagram to find genes which are commonly influenced by ME7 scrapie prion spread in the three tissues.
2021-12-31 | GSE157334 | GEO
Project description:Prion diseases are rare, neurological disorders caused by the misfolding of the cellular prion protein (PrPC). The misfolded conformers aggregate into cytotoxic fibrils (PrPSc) that facilitate the conversion of additional prion proteins into their misfolded form. Intracellular PrPSc aggregates primarily accumulate within late endosomes and lysosomes, organelles that participate in the degradation and turnover of a large subset of the proteome. Thus, intracellular accumulation of PrPSc aggregates have the potential to globally influence protein degradation kinetics. We have analyzed the proteome-wide effect of prion infection on protein degradation rates in N2a neuroblastoma cells by dynamic stable isotopic labeling with amino acids in cell culture (dSILAC) and bottom-up proteomics to quantify the degradation rates of more than 4700 proteins in prion-infected and uninfected cells. As expected, the degradation rate of the prion protein is significantly decreased upon aggregation in infected cells. The data indicate that dilution due to cell division, rather than degradation, is the dominant factor in clearance of PrPSc in infected N2a cells. Conversely, the degradation kinetics of the remainder of the N2a proteome generally increases upon infection. This effect occurs concurrently with increases in the cellular activities of autophagy and lysosomal hydrolases. The resulting enhancement in proteome flux may play a role in the survival of N2a cells during prion infection.
2021-09-08 | PXD014577 | Pride
Project description:Phospholipase C gamma 1 (PLC-γ1) occupies a critically important position in the T cell signaling pathway. While its functions as a regulator of both Ca2+ signaling and PKC-family kinases are well characterized, PLC-γ1’s role in the regulation of early T cell receptor signaling events is incomplete. Activation of the T cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from components of the signalosome complex to the apical kinase in the pathway, Lck. To determine the role, if any, of PLC-γ1 in these feedback networks, we performed a quantitative phosphoproteomic analysis of the PLC-γ1-deficient T cells. These data revealed a previously unappreciated role for PLC-γ1 in the positive regulation of Zap-70 and T cell receptor tyrosine phosphorylation. Conversely, PLC-γ1 negatively regulated the phosphorylation of signalosome associated proteins including previously established Lck substrate phosphorylation sites within this complex. While the positive and negative regulatory phosphorylation sites on Lck were largely unchanged, Tyr192 phosphorylation was elevated in Jgamma1. The data supports a model wherein Lck’s targeting, but not its kinase activity is altered by PLC-γ1, possibly through Lck Tyr192 phosphorylation.
2017-06-28 | PXD005165 | Pride
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. Experiment Overall Design: Primary sheep microglial cells were either inoculated with PrPSc (Inoc) or sham-inoculated (Mock) Experiment Overall Design: Three biological replicates per treatment. Experiment Overall Design: Three technical replicates per biological replicate. Experiment Overall Design: biological replicate: Inoc12A, Inoc12B.2, Inoc12C Experiment Overall Design: biological replicate: Mock12A, Mock12B.2, Mock12C Experiment Overall Design: technical replicate - extract: Inoc12A.1, Inoc12A.2, Inoc12A.3 Experiment Overall Design: technical replicate - extract: Inoc12B.2.1, Inoc12B.2.2, Inoc12B.2.3 Experiment Overall Design: technical replicate - extract: Inoc12C.1, Inoc12C.2, Inoc12C.3 Experiment Overall Design: technical replicate - extract: Mock12A.1, Mock12A.2, Mock12A.3 Experiment Overall Design: technical replicate - extract: Mock12B.2.1, Mock12B.2.2, Mock12B.2.3 Experiment Overall Design: technical replicate - extract: Mock12C.1, Mock12C.2, Mock12C.3
2008-11-04 | E-GEOD-12688 | biostudies-arrayexpress
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
Project description:The endogenous cellular prion protein (PrPC) can misfold into the scrapie isoform (PrPSc) and cause fatal infectious diseases. Despite significant research on the prion protein, both its normal function and whether alterations to that function play a critical role in prion diseases remain unknown. The protein consists of a predominantly alpha-helical C-terminal domain and an unstructured N-terminal domain that can coordinate Cu2+. Previous studies using NMR and EPR have revealed a tertiary association between the N-terminal domain and the C-terminal domain that we have hypothesized to be critical to the protein’s normal function. Here we investigated and quantified the inter-domain interactions within three different prion variants (wild type recombinant mouse PrPC, mutant delta central region (ΔCR), and disease mutant (E199K) after chemical cross-linking with a newly designed MS-cleavable reagent 1-(4-((2,5-Dioxopyrrolidin-1-yl)oxy)-4-oxobutyl)-4-(2-(3-methyl-3H-diazirin-3-yl)ethyl)-1,4-diazabicyclo[2.2.2] octane-1,4-diium (APDC4), followed by nHPLC(RP) and tandem MS analysis.
2020-06-16 | PXD012427 | Pride