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ResearchIn-Press PreviewAgingNeuroscience Open Access | 10.1172/JCI186432

Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice

Joie Lin,1 Julia A. Callender,1 Joshua E. Mayfield,1 Daniel B. McClatchy,2 Daniel Ojeda-Juárez,1 Mahsa Pourhamzeh,1 Katrin Soldau,1 Timothy D. Kurt,1 Garrett A. Danque,1 Helen K. Khuu,1 Josephina E. Ronson,1 Donald P. Pizzo,4 Yixing Du,5 Maxwell A. Gruber,1 Alejandro M. Sevillano,1 Jin Wang,1 Christina D. Orrú,6 Joy Chen,1 Gail Funk,1 Patricia Aguilar-Calvo,1 Brent D. Aulston,1 Subhojit Roy,1 Jong M. Rho,5 Jack D. Bui,1 Alexandra C. Newton,7 Stuart A. Lipton,8 Byron Caughey,6 Gentry N. Patrick,9 Kim Doré,5 John R. Yates III,2 and Christina J. Sigurdson1

1Department of Pathology, University of California at San Diego, La Jolla, United States of America

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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1Department of Pathology, University of California at San Diego, La Jolla, United States of America

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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1Department of Pathology, University of California at San Diego, La Jolla, United States of America

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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1Department of Pathology, University of California at San Diego, La Jolla, United States of America

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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4Pathology, University of California at San Diego, La Jolla, United States of America

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7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

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7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

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8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

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4Pathology, University of California at San Diego, La Jolla, United States of America

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6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

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1Department of Pathology, University of California at San Diego, La Jolla, United States of America

2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

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4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

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2Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

5Department of Neurosciences, University of California at San Diego, La Jolla, United States of America

6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

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4Pathology, University of California at San Diego, La Jolla, United States of America

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6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

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6Laboratory of Persistent Viral Diseases, NIH, Hamilton, United States of America

7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

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4Pathology, University of California at San Diego, La Jolla, United States of America

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7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

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3Department of Pathology, University of California at San Diego, La jolla, United States of America

4Pathology, University of California at San Diego, La Jolla, United States of America

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7Department of Pharmacology, University of California at San Diego, La Jolla, United States of America

8Department of Molecular Medicine and Neuroscience, Scripps Research Institute, La Jolla, United States of America

9Department of Biology, University of California at San Diego, La Jolla, United States of America

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Published April 4, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186432.
Copyright © 2025, Lin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 4, 2025 - Version history
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Abstract

Neuronal hyperexcitability precedes synapse loss in certain neurodegenerative diseases, yet the synaptic membrane interactions and downstream signaling events remain unclear. The disordered amino terminus of the prion protein (PrPC) has been implicated in aberrant signaling in prion and Alzheimer’s disease. To disrupt neuronal interactions and signaling linked to the amino terminus, here we CRISPR-engineered a knock-in mouse expressing mutant PrPC (G92N), generating an N-linked glycosylation site between two functional motifs. Mice developed seizures and necrosis of hippocampal pyramidal neurons, similar to prion-infected mice and consistent with excitotoxicity. Phosphoproteomics revealed phosphorylated glutamate receptors and calcium-sensitive kinases, including protein kinase C (PKC). Additionally, 92N-PrPC-expressing neurons show persistent calcium influx as well as dendritic beading, which was rescued by an NMDA receptor antagonist. Finally, survival of Prnp92N mice was prolonged by blocking active NMDA receptor channels. We propose dysregulated PrPC – NMDA receptor - induced signaling can trigger excitatory – inhibitory imbalance, spongiform degeneration, and neurotoxicity, and that calcium dysregulation is central to PrPC-linked neurodegeneration.

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View Video S1. Generalized seizures in a Prnp92N mouse. Terminal P24 Prnp92N mouse displays hyperactivity, behavioral arrest, ataxia, myoclonic twitches (neck jerks), and straub tail.

View Video S2. Tonic-clonic, generalized (grand mal) seizure in a Prnp92N mouse. Terminal P24 Prnp92N mouse exhibiting paddling behavior.

View Video S4. Terminal Prnp-/- mice transduced with AAV-hSyn1-Prnp92N show severe neurological phenotype. P33 AAV-92N mice at 11 days post-inoculation are severely kyphotic and show myoclonic twitches (neck and full body jerks), behavioral arrest, stiff gait, ataxia, and straub tail.

View Video S5. Age-matched Prnp-/- mice transduced with AAV-hSyn1-PrnpWT are neurologically normal. P33 AAV-WT mice at 11 days post-inoculation are healthy with no behavioral phenotype.

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View Video S3. PrnpWT mouse at P24.

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  • Version 1 (April 4, 2025): In-Press Preview
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