Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs

We then used these data as input into the L1000 and P100 databases of transcriptomic and proteomic drug signatures, leading to the discovery of 17 compounds that were able to prevent PrPSc-induced spine retraction. These compounds converged on three protein kinase targets: Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), and glycogen synthase kinase 3β (GSK3β). Using immunocytochemical staining, we confirmed that PrPSc treatment of hippocampal neurons induced phosphorylation of the three kinases and caused their rapid translocation to dendritic spines.

Along with N-methyl-D-aspartate receptors (NMDARs) on the neuronal surface, which trigger an initial influx of Ca2+ in response to PrPSc, these kinases constitute key nodes in a signaling network that mediates prion synaptotoxicity. Taken together, our results provide new insights into the mechanisms of prion neurotoxicity, and they identify novel molecular targets and inhibitory compounds that can be utilized for therapy of prion diseases.