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Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice

ABSTRACT: Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific cell types and brain regions. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite appearing normal. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated reduced synthesis of ribosomal and mitochondrial components, 2) glutamatergic neurons showed increased expression of cytoskeletal genes, and 3) GABAergic neurons revealed reduced expression of circadian rhythm genes. These data demonstrate that early translatome responses to neurodegeneration emerge prior to conventional markers of disease and are cell type-specific. Therapeutic strategies may need to target multiple pathways in specific populations of cells, early in disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE189527 | GEO | 2022/06/13

REPOSITORIES: GEO

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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.

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Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice

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