Prions induce an early Arc response and a subsequent reduction in mGluR5 in the hippocampus.
Abstract
Synapse dysfunction and loss are central features of neurodegenerative diseases, caused in part by the accumulation of protein oligomers. Amyloid-β, tau, prion, and α-synuclein oligomers bind to the cellular prion protein (PrP<sup>C),</sup> resulting in the activation of macromolecular complexes and signaling at the post-synapse, yet the early signaling events are unclear. Here we sought to determine the early transcript and protein alterations in the hippocampus during the pre-clinical stages of prion disease. 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 male, prion-infected mice, Arc/Arg-3.1 protein was increased early (40% of the incubation period), and by mid-disease (pre-clinical), phosphorylated AMPA receptors (pGluA1-S845) were increased and metabotropic glutamate receptors (mGluR5 dimers) were markedly reduced in the hippocampus. Notably, sporadic Creutzfeldt-Jakob disease (sCJD) post-mortem cortical samples also showed low levels of mGluR5 dimers. Together, these findings suggest that prions trigger an early Arc response, followed by an increase in phosphorylated GluA1 and a reduction in mGluR5 receptors.
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Prions induce an early Arc response in the hippocampus of prion-infected mice
Mus musculus6 data files
| File | Type | Size |
|---|---|---|
| 2712_1_S25_L003_R1_001.fastq.gz | RNA-Seq | 1.6 GB |
| 2712_2_S26_L003_R1_001.fastq.gz | RNA-Seq | 2.2 GB |
| 2712_3_S27_L003_R1_001.fastq.gz | RNA-Seq | 1.6 GB |
| 2713_2_S28_L003_R1_001.fastq.gz | RNA-Seq | 2.0 GB |
| 2713_3_S29_L003_R1_001.fastq.gz | RNA-Seq | 1.9 GB |
| 2713_4_S30_L003_R1_001.fastq.gz | RNA-Seq | 1.5 GB |
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