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| Status |
Public on Nov 09, 2012 |
| Title |
Early Mechanisms of Pathobiology are Revealed by Transcriptional Temporal Dynamics in Hippocampal CA1 Neurons of Prion Infected Mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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 ≥ 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.
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| Contributor(s) |
Majer A, Medina SJ, Niu Y, Abrenica B, Manguiat KJ, Frost KL, Phillipson CS, Sorensen DL, Booth SA |
| Citation(s) |
23144617 |
| Submission date |
Dec 19, 2011 |
| Last update date |
May 10, 2018 |
| Contact name |
Sarah Jean Medina |
| E-mail(s) |
sarah_medina@phac-aspc.gc.ca
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| Organization name |
Public Health Agency of Canada
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| Department |
Molecular PathoBiology
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| Lab |
National Microbiology Laboratory
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| Street address |
1015 Arlington Street
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| City |
Winnipeg |
| State/province |
Manitoba |
| ZIP/Postal code |
R3E 3R2 |
| Country |
Canada |
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| Platforms (1) |
| GPL4134 |
Agilent-014868 Whole Mouse Genome Microarray 4x44K G4122F (Feature Number version) |
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| Samples (38)
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| GSM850605 |
CA1 cells_RML_vs_PBS_dpi 40_rep6_2 |
| GSM850606 |
CA1 cells_RML_vs_PBS_dpi 70_rep1_1 |
| GSM850607 |
CA1 cells_RML_vs_PBS_dpi 70_rep1_2 |
| GSM850608 |
CA1 cells_RML_vs_PBS_dpi 70_rep2_1 |
| GSM850609 |
CA1 cells_RML_vs_PBS_dpi 70_rep2_2 |
| GSM850610 |
CA1 cells_RML_vs_PBS_dpi 70_rep3_1 |
| GSM850611 |
CA1 cells_RML_vs_PBS_dpi 70_rep3_2 |
| GSM850612 |
CA1 cells_RML_vs_PBS_dpi 70_rep4_1 |
| GSM850613 |
CA1 cells_RML_vs_PBS_dpi 70_rep4_2 |
| GSM850614 |
CA1 cells_RML_vs_PBS_dpi 90_rep1_1 |
| GSM850615 |
CA1 cells_RML_vs_PBS_dpi 90_rep1_2 |
| GSM850616 |
CA1 cells_RML_vs_PBS_dpi 90_rep2_1 |
| GSM850617 |
CA1 cells_RML_vs_PBS_dpi 90_rep2_2 |
| GSM850618 |
CA1 cells_RML_vs_PBS_dpi 90_rep3_1 |
| GSM850619 |
CA1 cells_RML_vs_PBS_dpi 90_rep3_2 |
| GSM850620 |
CA1 cells_RML_vs_PBS_dpi 100_rep1_1 |
| GSM850621 |
CA1 cells_RML_vs_PBS_dpi 100_rep1_2 |
| GSM850622 |
CA1 cells_RML_vs_PBS_dpi 100_rep2_1 |
| GSM850623 |
CA1 cells_RML_vs_PBS_dpi 100_rep2_2 |
| GSM850624 |
CA1 cells_RML_vs_PBS_dpi 110_rep1_1 |
| GSM850625 |
CA1 cells_RML_vs_PBS_dpi 110_rep1_2 |
| GSM850626 |
CA1 cells_RML_vs_PBS_dpi 110_rep2_1 |
| GSM850627 |
CA1 cells_RML_vs_PBS_dpi 110_rep2_2 |
| GSM850628 |
CA1 cells_RML_vs_PBS_dpi 130_rep1_1 |
| GSM850629 |
CA1 cells_RML_vs_PBS_dpi 130_rep1_2 |
| GSM850630 |
CA1 cells_RML_vs_PBS_dpi 130_rep2_1 |
| GSM850631 |
CA1 cells_RML_vs_PBS_dpi 130_rep2_2 |
| GSM850632 |
CA1 cells_RML_vs_PBS_dpi 130_rep3_1 |
| GSM850633 |
CA1 cells_RML_vs_PBS_dpi 130_rep3_2 |
| GSM850634 |
CA1 cells_RML_vs_PBS_dpi 130_rep4_1 |
| GSM850635 |
CA1 cells_RML_vs_PBS_dpi 130_rep4_2 |
| GSM850636 |
CA1 cells_RML_vs_PBS_dpi EP_rep1_1 |
| GSM850637 |
CA1 cells_RML_vs_PBS_dpi EP_rep1_2 |
| GSM850638 |
CA1 cells_RML_vs_PBS_dpi EP_rep2_1 |
| GSM850639 |
CA1 cells_RML_vs_PBS_dpi EP_rep2_2 |
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| Relations |
| BioProject |
PRJNA151391 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE34530_RAW.tar |
420.2 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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