ArticleThe Journal of clinical investigation2025
Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model.bioRxiv : the preprint server for biology · 2026Article
- Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs.PLoS pathogens · 2026Article
- Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs.bioRxiv : the preprint server for biology · 2026Article
- One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Emerging Therapeutic Strategies in Intracerebral Hemorrhage: Enhancing Neurogenesis and Functional Recovery.MedComm · 2025Review
- NMDA Receptors Coordinate Metabolic Reprogramming and Mitophagy in Schwann Cells to Promote Peripheral Nerve Regeneration.Research (Washington, D.C.) · 2025Article
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Authors and funding
31 authors.
Funding
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, 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.