Prions induce an early Arc response and a subsequent reduction in mGluR5 in the hippocampus

Daniel Ojeda-Juárez; Jessica A. Lawrence; Katrin Soldau; Donald P. Pizzo; Emily Wheeler; Patricia Aguilar-Calvo; Helen Khuu; Joy Chen; Adela Malik; Gail Funk; Percival Nam; Henry Sanchez; Michael D. Geschwind; Chengbiao Wu; Gene W. Yeo; Xu Chen; Gentry N. Patrick; Christina J. Sigurdson

Neurobiology of Disease (Oct 2022)

Prions induce an early Arc response and a subsequent reduction in mGluR5 in the hippocampus

Daniel Ojeda-Juárez,
Jessica A. Lawrence,
Katrin Soldau,
Donald P. Pizzo,
Emily Wheeler,
Patricia Aguilar-Calvo,
Helen Khuu,
Joy Chen,
Adela Malik,
Gail Funk,
Percival Nam,
Henry Sanchez,
Michael D. Geschwind,
Chengbiao Wu,
Gene W. Yeo,
Xu Chen,
Gentry N. Patrick,
Christina J. Sigurdson

Affiliations

Daniel Ojeda-Juárez: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Jessica A. Lawrence: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Katrin Soldau: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Donald P. Pizzo: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Emily Wheeler: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
Patricia Aguilar-Calvo: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Helen Khuu: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Joy Chen: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Adela Malik: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Gail Funk: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Percival Nam: Department of Pathology, University of California San Diego, La Jolla, CA, USA
Henry Sanchez: Department of Pathology, Division of Neuropathology, University of California San Francisco, San Francisco, CA, USA
Michael D. Geschwind: Department of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA
Chengbiao Wu: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Gene W. Yeo: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
Xu Chen: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
Gentry N. Patrick: Division of Biological Sciences, Section of Neurobiology, University of California San Diego, La Jolla, CA, USA
Christina J. Sigurdson: Department of Pathology, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Pathology, Microbiology and Immunology, University of California Davis, Davis, CA, USA; Corresponding author at: Department of Pathology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0612, USA.

Journal volume & issue: Vol. 172
p. 105834

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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