Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs - PubMed
4 hours ago
- #prion disease
- #drug discovery
- #neurotoxicity
- Prion neurotoxicity mechanisms remain unclear, with synaptic loss as an early event in prion disease.
- A neuronal cell culture model shows PrPSc exposure activates an NMDAR/p38 MAPK pathway, causing synaptic loss and spine retraction.
- Phosphoproteomic and transcriptomic analyses identified kinase targets: CaMKII, PKC, and GSK3β, phosphorylated and translocated to spines upon PrPSc treatment.
- 17 compounds from drug signature databases prevented PrPSc-induced spine retraction, converging on CaMKII, PKC, and GSK3β inhibition.
- NMDARs and these kinases form a signaling network mediating prion synaptotoxicity, offering new therapeutic targets for prion diseases.