Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice
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, we CRISPR-engineered a knockin mouse expressing mutant PrPC (G92N), generating an N-linked glycosylation site between 2 functional motifs. Mice developed seizures and necrosis of hippocampal pyramidal neurons, similar to prion-infected mice and consistent with excitotoxicity. Phosphoproteomics analysis revealed phosphorylated glutamate receptors and calcium-sensitive kinases, including protein kinase C (PKC). Additionally, 92N-PrPC-expressing neurons showed persistent calcium influx as well as dendritic beading, which was rescued by an N-methyl-d-aspartate receptor (NMDAR) antagonist. Finally, survival of Prnp92N mice was prolonged by blocking active NMDAR channels. We propose that dysregulated PrPC-NMDAR-induced signaling can trigger an excitatory-inhibitory imbalance, spongiform degeneration, and neurotoxicity and that calcium dysregulation is central to PrPC-linked neurodegeneration.
Authors
- Helen Khuu
- Jong M. Rho (ORCID: https://orcid.org/0000-0001-9886-9924)
- Patricia Aguilar‐Calvo
- Byron Caughey (ORCID: https://orcid.org/0000-0002-3928-6101)
- Gentry N. Patrick
- Yixing Du
- Brent Aulston (ORCID: https://orcid.org/0000-0001-6865-0577)
- Kim Doré (ORCID: https://orcid.org/0000-0001-6263-367X)
- John R. Yates (ORCID: https://orcid.org/0000-0001-5267-1672)
- Christina D. Orrú (ORCID: https://orcid.org/0000-0001-7253-2944)
- M. Gruber
- Joy Chen (ORCID: https://orcid.org/0000-0002-1318-1766)
- Donald P. Pizzo (ORCID: https://orcid.org/0000-0002-8022-3604)
- Alejandro M. Sevillano (ORCID: https://orcid.org/0000-0002-2107-2375)
- Daniel Ojeda-Juárez (ORCID: https://orcid.org/0000-0002-0722-2509)
- Julia A. Callender (ORCID: https://orcid.org/0000-0003-4285-8403)
- Christina J. Sigurdson (ORCID: https://orcid.org/0000-0002-1770-0965)
- Katrin Soldau
- Joshua E. Mayfield (ORCID: https://orcid.org/0000-0002-5253-0084)
- Gail Funk
- Daniel B. McClatchy (ORCID: https://orcid.org/0000-0002-0288-5645)
- Stuart A. Lipton (ORCID: https://orcid.org/0000-0002-3490-1259)
- Mahsa Pourhamzeh (ORCID: https://orcid.org/0000-0002-6712-7220)
- Subhojit Roy (ORCID: https://orcid.org/0000-0002-1571-2735)
- Jack D. Bui (ORCID: https://orcid.org/0000-0002-9324-368X)
- Alexandra C. Newton (ORCID: https://orcid.org/0000-0002-2906-3705)
- Timothy D. Kurt
- Jonathan H. Lin (ORCID: https://orcid.org/0000-0002-7438-6941)
- Jin Wang (ORCID: https://orcid.org/0000-0003-4525-9924)
- Garrett A Danque
- Josephina E Ronson
Institutions
- Scripps Research Institute (US)
- Global Viral (US)
- University of California San Diego (US)
- National Institute of Allergy and Infectious Diseases (US)
- University of California, Davis (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-04-04
- DOI
- https://doi.org/10.1172/jci186432
- Citations
- 5
- Primary Topic
- Prion Diseases and Protein Misfolding
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Adamas Pharmaceuticals
- National Institutes of Health
- Forest Laboratories
- Allergan
- University of California, San Diego
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke
- Chao Family Comprehensive Cancer Center