Neurons and astrocytes elicit brain region specific transcriptional responses to prion disease in the murine CA1 and thalamus
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ABSTRACT:
PROVIDER: PRJNA830500 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR18858500_1.fastq.gz | Fastqsanger.gz | |||
| SRR18858500_2.fastq.gz | Fastqsanger.gz | |||
| SRR18858501_1.fastq.gz | Fastqsanger.gz | |||
| SRR18858501_2.fastq.gz | Fastqsanger.gz | |||
| SRR18858502_1.fastq.gz | Fastqsanger.gz |
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Project description:Progressive dysfunction and loss of neurons ultimately culminates in the symptoms and eventual fatality of prion disease, yet the pathways and mechanisms that lead to neuronal degeneration remain elusive. Here, we used RNAseq to profile transcriptional changes in microdissected CA1 and thalamus brain tissues from prion infected mice. Numerous transcripts were altered during clinical disease, whereas very few transcripts were reliably altered at pre-clinical time points. Prion altered transcripts were assigned to broadly defined brain cell types and we noted a strong transcriptional signature that was affiliated with reactive microglia and astrocytes. While very few neuronal transcripts were common between the CA1 and thalamus, we described transcriptional changes in both regions that were related to synaptic dysfunction. Using transcriptional profiling to compare how different neuronal populations respond during prion disease may help decipher mechanisms that lead to neuronal demise and should be investigated with greater detail.
2022-04-28 | GSE201249 | GEO
Project description:Progressive dysfunction and loss of neurons ultimately culminates in the symptoms and eventual fatality of prion disease, yet the pathways and mechanisms that lead to neuronal degeneration remain elusive. Here, we used RNAseq to profile transcriptional changes in microdissected CA1 and thalamus brain tissues from prion infected mice. Numerous transcripts were altered during clinical disease, whereas very few transcripts were reliably altered at pre-clinical time points. Prion altered transcripts were assigned to broadly defined brain cell types and we noted a strong transcriptional signature that was affiliated with reactive microglia and astrocytes. While very few neuronal transcripts were common between the CA1 and thalamus, we described transcriptional changes in both regions that were related to synaptic dysfunction. Using transcriptional profiling to compare how different neuronal populations respond during prion disease may help decipher mechanisms that lead to neuronal demise and should be investigated with greater detail.
| S-EPMC9149297 | biostudies-literature
Project description:Fatal familial insomnia (FFI) is a special subtype of genetic human prion diseases that is caused by the D178N mutation of the prion protein gene (PRNP). In this study, global expression patterns of the thalamus and parietal cortex from three patients with FFI were analyzed by Affymetrix Human Genome U133+ 2.0 chip. We used microarrays to detail the global gene expression in tissues from normal human and FFI patients thalamus, or parietal lobe. Tissues from normal human and FFI patients' thalamus, or parietal lobe were for RNA extraction and hybridization on Affymetrix microarrays.
2015-08-30 | E-GEOD-40562 | biostudies-arrayexpress
Project description:Prion diseases typically have long pre-clinical incubation periods during which time the infectious prion particle and infectivity steadily propagate in the brain. Abnormal neuritic sprouting and synaptic deficits are apparent during pre-clinical disease, however, gross neuronal loss is not detected until the onset of the clinical phase. The molecular events that accompany early neuronal damage and ultimately conclude with neuronal death remain obscure. In this study, we used laser capture microdissection to isolate hippocampal CA1 neurons and then determined their pre-clinical transcriptional response during infection. We found that gene expression within these neurons is dynamic and characterized by distinct phases of activity. A major cluster of genes is altered during pre-clinical disease after which expression either returns to basal levels, or alternatively undergoes a direct reversal during clinical disease. Strikingly, we show that this cluster contains a signature highly reminiscent of synaptic N-methyl-D-aspartic acid (NMDA) receptor signaling and the activation of neuroprotective pathways. Additionally, genes involved in neuronal projection and dendrite development were also altered throughout the disease, culminating in a general decline of gene expression for synaptic proteins. Similarly, deregulated miRNAs such as miR-132-3p, miR-124a-3p, miR-16-5p, miR-26a-5p, miR-29a-3p and miR-140-5p follow concomitant patterns of expression. This is the first in depth genomic study describing the pre-clinical response of hippocampal neurons to early prion replication. Our findings suggest that prion replication results in the persistent stimulation of a programmed response, at least in part mediated by synaptic NMDA receptor activity that initially promotes cell survival and neurite remodelling. However, this response is terminated prior to the onset of clinical symptoms in the infected hippocampus, seemingly pointing to a critical juncture in the disease. Manipulation of these early neuroprotective pathways may redress the balance between degeneration and survival, providing a potential inroad for treatment. The CA1 hippocampal region was dissected out using LCM and RNA was extracted from these samples. In total, 6 different time points were screened for both RNA and miRNA expression levels in prion infected and control animals. Gene expression profiles from 6 time points (n M-bM-^IM-% 2) were determined using whole mouse 4x44K arrays. We successfully validated a subset of candidate genes that were deregulated during early prion disease. We performed a similar assessment of temporal miRNAs expression levels throughout the infection using the TLDA platform which was further validated by individual real-time PCR assays. In parallel, immunoctyochemistry was used to characterize the cellular presence of astrocytes, microglial and neurons in the CA1 region throughout the disease which correlated well with both mRNA and miRNA expression profiles. Staining for the PrPRes and neuronal toxicity levels was also performed to determine the spatial and temporal PrPRes deposition and assess the level of neuronal death that occurs in the hippocampus, respectively. Using bioinformatic methods, potential pathways that were implicated by our data to be deregulated during early prion disease were presented while potential miRNA regulation of some of these candidate genes implicated in these pathways was also included.
2012-11-09 | E-GEOD-34530 | biostudies-arrayexpress
Project description:Fatal familial insomnia (FFI) is a special subtype of genetic human prion diseases that is caused by the D178N mutation of the prion protein gene (PRNP). In this study, global expression patterns of the thalamus and parietal cortex from three patients with FFI were analyzed by Affymetrix Human Genome U133+ 2.0 chip. We used microarrays to detail the global gene expression in tissues from normal human and FFI patients thalamus, or parietal lobe.
2015-08-30 | GSE40562 | GEO
Project description:Prion diseases typically have long pre-clinical incubation periods during which time the infectious prion particle and infectivity steadily propagate in the brain. Abnormal neuritic sprouting and synaptic deficits are apparent during pre-clinical disease, however, gross neuronal loss is not detected until the onset of the clinical phase. The molecular events that accompany early neuronal damage and ultimately conclude with neuronal death remain obscure. In this study, we used laser capture microdissection to isolate hippocampal CA1 neurons and then determined their pre-clinical transcriptional response during infection. We found that gene expression within these neurons is dynamic and characterized by distinct phases of activity. A major cluster of genes is altered during pre-clinical disease after which expression either returns to basal levels, or alternatively undergoes a direct reversal during clinical disease. Strikingly, we show that this cluster contains a signature highly reminiscent of synaptic N-methyl-D-aspartic acid (NMDA) receptor signaling and the activation of neuroprotective pathways. Additionally, genes involved in neuronal projection and dendrite development were also altered throughout the disease, culminating in a general decline of gene expression for synaptic proteins. Similarly, deregulated miRNAs such as miR-132-3p, miR-124a-3p, miR-16-5p, miR-26a-5p, miR-29a-3p and miR-140-5p follow concomitant patterns of expression. This is the first in depth genomic study describing the pre-clinical response of hippocampal neurons to early prion replication. Our findings suggest that prion replication results in the persistent stimulation of a programmed response, at least in part mediated by synaptic NMDA receptor activity that initially promotes cell survival and neurite remodelling. However, this response is terminated prior to the onset of clinical symptoms in the infected hippocampus, seemingly pointing to a critical juncture in the disease. Manipulation of these early neuroprotective pathways may redress the balance between degeneration and survival, providing a potential inroad for treatment.
2012-11-09 | GSE34530 | GEO
Project description:The thalamus may be the critical brain area involved in sensory gating and the relay of respiratory mechanical information to the cerebral cortex for the conscious awareness of breathing. We hypothesized that respiratory mechanical stimuli in the form of tracheal occlusions would modulate the gene expression profile of the thalamus. Specifically, it was reasoned that conditioning to the respiratory loading would induce a state change in the medial thalamus consistent with a change in sensory gating and the activation of molecular pathways associated with learning and memory. In addition, respiratory loading is stressful and thus should elicit changes in gene expressions related to stress, anxiety, and depression. Rats were instrumented with inflatable tracheal cuffs. Following surgical recovery, they underwent ten days (5 days/week) of transient tracheal occlusion conditioning. On day 10, the animals were sacrificed and the brains removed. The medial thalamus was dissected and microarray analysis of gene expression performed. Tracheal obstruction conditioning modulated a total of 661 genes (p < 0.05, log2 fold change ≥ 0.58), 250 genes were down-regulated and 411 up-regulated. There was a significant down-regulation of GAD1, GAD2 and HTR1A, HTR2A genes. CCK, PRKCG, mGluR4, and KCJN9 genes were significantly up-regulated. Some of these genes have been associated with anxiety and depression, while others have been shown to play a role in switching between tonic and burst firing modes in the thalamus and thus may be involved in gating of the respiratory stimuli. Furthermore, gene ontology and pathway analysis showed a significant modulation of learning and memory pathways. These results support the hypothesis that the medial thalamus is involved in the respiratory sensory neural pathway due to the state change of its gene expression profile following repeated tracheal occlusions. Four experimental animals that received tracheal occlusions and four surgical control animals were used. A reference design was used to compare all samples.
2010-11-05 | E-GEOD-25152 | biostudies-arrayexpress
Project description:Nuclei of the mammalian thalamus are aggregations of neurons with unique architectures and input-output connections, yet the molecular determinants of their organizational specificity remain unknown. By comparing expression profiles of thalamus and cerebral cortex in adult rhesus monkeys we identified transcripts that are unique to dorsal thalamus or to individual nuclei within it. Real-time quantitative polymerase chain reaction and in situ hybridization analyses confirmed the findings. Expression profiling of individual nuclei microdissected from the dorsal thalamus revealed additional subsets of nucleus-specific genes. Functional annotation using Gene Ontology (GO) vocabulary and Ingenuity Pathway analysis revealed over-representation of GO categories related to development, morphogenesis, cell-cell interactions, and extracellular matrix within the thalamus- and nucleus-specific genes-many involved in the Wnt signaling pathway. Examples included the transcription factor TCF7L2, localized exclusively to excitatory neurons, a calmodulin-binding protein PCP4, the bone extracellular matrix molecules SPP1 and SPARC, and other genes involved in axon outgrowth and cell matrix interactions. Other nucleus-specific genes such as CBLN1 are involved in synaptogenesis. The genes identified likely underlie nuclear specification, cell phenotype and connectivity during development and their maintenance in the adult thalamus. Experiment Overall Design: To determine the molecular underpinnings of nuclear specificity in the dorsal thalamus we isolated micro-punches of tissue from nucleus-specific regions and processed them for microarray analysis. Replicate samples from 5 separate dorsal thalamic nuclei were processed and compared to identify genes unique to each region. Affymetrix U133A Gene Chips were used. All of the samples were isolated from untreated adult monkey brain.
2008-06-15 | E-GEOD-6708 | biostudies-arrayexpress
Project description:Chronic neuroinflammation involves reactive microgliosis and astrogliosis, and is regarded as a common pathological hallmark of neurodegenerative diseases including Alzheimer's, Parkinson's, ALS and prion diseases. Reactive astrogliosis, routinely observed immunohistochemically as an increase in glial fibrillary acidic protein (GFAP) signal, is a well-documented feature of chronic neuroinflammation associated with neurodegenerative diseases. Recent studies on single-cell transcriptional profiling of a mouse brain revealed that, under normal conditions, several distinct subtypes of astrocytes with regionally specialized distribution exist. However, it remains unclear whether astrocytic response to pro-inflammatory pathological conditions is uniform across whole brain or is region-specific. The current study compares the response of microglia and astrocytes to prions in mice infected with 22L mouse-adapted prion strain. While the intensity of reactive microgliosis correlated well with the extent of PrPSc deposition, reactive astrogliosis displayed a different, region-specific pattern. In particular, the thalamus and stratum oriens of hippocampus, which are both affected by 22L prions, displayed strikingly different response of astrocytes to PrPSc. Astrocytes in stratum oriens of hippocampus responded to accumulation of PrPSc with visible hypertrophy and increased GFAP, while in the thalamus, despite stronger PrPSc signal, the increase of GFAP was milder than in hippocampus, and the change in astrocyte morphology was less pronounced. The current study suggests that astrocyte response to prion infection is heterogeneous and, in part, defined by brain region. Moreover, the current work emphasizes the needs for elucidating region-specific changes in functional states of astrocytes and exploring the impact of these changes to chronic neurodegeneration.
| S-EPMC6794343 | biostudies-literature
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