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A High-content Assay for Monitoring AMPA Receptor Trafficking
Published on: January 28, 2019
Prions induce an early Arc response and a subsequent reduction in mGluR5 in the hippocampus
Daniel Ojeda-Juárez1, Jessica A Lawrence1, Katrin Soldau1
1Department of Pathology, University of California San Diego, La Jolla, CA, USA.
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 (PrPC), 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.
Insights
Prion diseases disrupt synapses. Early in prion disease, the Arc gene is upregulated, followed by changes in AMPA and mGluR5 receptors, offering insights into pre-clinical neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Prion Disease Research
Background:
- Synapse dysfunction and loss are hallmarks of neurodegenerative diseases, often linked to protein oligomer accumulation.
- Oligomers of amyloid-β, tau, prion, and α-synuclein interact with the cellular prion protein (PrPC), initiating post-synaptic signaling, but early events remain poorly understood.
Purpose of the Study:
- To investigate early transcriptomic and proteomic alterations in the hippocampus during the pre-clinical stages of prion disease.
- To identify key molecular events preceding observable disease symptoms in prion-infected models.
Main Methods:
- Transcriptomic analysis of early-stage prion-infected mouse hippocampus.
- Longitudinal proteomic study in prion-infected mice, focusing on synaptic proteins.
- Analysis of post-mortem cortical samples from sporadic Creutzfeldt-Jakob disease (sCJD) patients.
Main Results:
- Significant upregulation of immediate early genes, including the synaptic activity response gene Arc/Arg3.1, was identified.
- Arc/Arg-3.1 protein levels increased early in prion-infected mice.
- Mid-disease stages showed increased phosphorylated AMPA receptors (pGluA1-S845) and markedly reduced metabotropic glutamate receptors (mGluR5 dimers) in the hippocampus. Similar reductions in mGluR5 dimers were observed in sCJD samples.
Conclusions:
- Prions initiate an early Arc response in the hippocampus.
- Subsequent synaptic alterations include increased phosphorylated AMPA receptors and decreased mGluR5 receptors during pre-clinical prion disease.
- These molecular changes may represent early pathological events in prion-induced neurodegeneration.
