ArticlePLoS pathogens2018
Prions activate a p38 MAPK synaptotoxic signaling pathway.
Article in PLoS pathogens, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 74 citations in OpenAlex.
- PrPStem cell reports · 2026Article
- Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs.PLoS pathogens · 2026Article
- Enhanced lysosomal activity prevents infection with PrPThe Journal of biological chemistry · 2026Article
- Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs.bioRxiv : the preprint server for biology · 2026Article
- Presymptomatic pharmacological inhibition of mGluR5 improves survival in a mouse model of prion diseases.Acta neuropathologica communications · 2026Article
- Membrane-anchored PrPSc is the trigger for prion synaptotoxicity.PLoS pathogens · 2026Article
- One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Pathological and Functional Brain Amyloids: A New Concept Explaining the Differences.International journal of molecular sciences · 2025Review
- Knockout of P2Y12 receptor facilitates neuronal envelopment by reactive microglia and accelerates prion disease.Journal of neuroinflammation · 2025Article
- Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice.The Journal of clinical investigation · 2025Article
- Prion replication in organotypic brain slice cultures is distinct from in vivo inoculation and is species dependent.Acta neuropathologica communications · 2025Article
- Knockout of P2Y12 receptor facilitates microglia-neuron body-to-body interactions and accelerates prion disease.bioRxiv : the preprint server for biology · 2025Article
- Reactive Microglia and Astrocytes as Therapeutic Targets in Prion Diseases.Sub-cellular biochemistry · 2025Review
- Limbic system synaptic dysfunctions associated with prion disease onset.Acta neuropathologica communications · 2024Article
- Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer's disease.Nature communications · 2024Article
- Prion protein pathology in Ubiquilin 2 models of ALS.Neurobiology of disease · 2024Article
- Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease.Stem cell reports · 2024Article
- Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding.ACS chemical neuroscience · 2024Article
- New Light on Prions: Putative Role of PrPInternational journal of molecular sciences · 2024Review
- Creutzfeldt-Jakob disease and other prion diseases.Nature reviews. Disease primers · 2024Review
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
Synaptic degeneration is one of the earliest pathological correlates of prion disease, and it is a major determinant of the progression of clinical symptoms. However, the cellular and molecular mechanisms underlying prion synaptotoxicity are poorly understood. Previously, we described an experimental system in which treatment of cultured hippocampal neurons with purified PrPSc, the infectious form of the prion protein, induces rapid retraction of dendritic spines, an effect that is entirely dependent on expression of endogenous PrPC by the target neurons. Here, we use this system to dissect pharmacologically the underlying cellular and molecular mechanisms. We show that PrPSc initiates a stepwise synaptotoxic signaling cascade that includes activation of NMDA receptors, calcium influx, stimulation of p38 MAPK and several downstream kinases, and collapse of the actin cytoskeleton within dendritic spines. Synaptic degeneration is restricted to excitatory synapses, spares presynaptic structures, and results in decrements in functional synaptic transmission. Pharmacological inhibition of any one of the steps in the signaling cascade, as well as expression of a dominant-negative form of p38 MAPK, block PrPSc-induced spine degeneration. Moreover, p38 MAPK inhibitors actually reverse the degenerative process after it has already begun. We also show that, while PrPC mediates the synaptotoxic effects of both PrPSc and the Alzheimer's Aβ peptide in this system, the two species activate distinct signaling pathways. Taken together, our results provide powerful insights into the biology of prion neurotoxicity, they identify new, druggable therapeutic targets, and they allow comparison of prion synaptotoxic pathways with those involved in other neurodegenerative diseases.
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