Prion diseases are fatal neurodegenerative disorders that affect both humans and animals. These diseases are caused by PrPSc, a misfolded and infectious isoform of the normal cellular prion protein (PrPC), which propagates by a self-templating mechanism. While considerable progress has been made in understanding prion propagation and infectivity, the early cellular events that initiate prion-induced synaptic loss and neurodegeneration remain poorly defined.
A recent publication in PLoS Pathogens from the Harris lab, led by graduate student Jean Gatdula, focused on the initial molecular events on the neuronal surface that initiate prion synaptotoxicity. Using a specialized neuronal culture system that allows direct measurements of synaptic integrity, they found that experimental manipulations that blocked formation of pathogenic PrPSc on the neuronal surface prevented synaptic damage. Thus, membrane-attached PrPSc molecules are directly responsible for triggering a prion synaptotoxic signaling cascade, presumably by interacting with other proteins or lipids on the membrane surface. These results not only illuminate basic pathogenic mechanisms, but they suggest a novel therapeutic approach using PrP molecules that are locked in the PrPC conformation.