The most common cause of inherited prion diseases is the E200K mutation of the prion protein (PrP). It is often thought that this mutation causes disease by making PrP more susceptible to misfolding into a pathogenic shape (PrPSc). However, new research has found that the architecture of neuron-to-neuron contact sites, known as synapses, is altered in neurons expressing this mutant PrP in the absence of PrPSc. This suggests that a loss or change in PrP function may contribute to the disease phenotype.