Misfolding leads the way to unraveling signaling pathways in the pathophysiology of prion diseases.

A misfolded version of the prion protein represents an essential component in the pathophysiology of fatal neurodegenerative prion diseases, which affect humans and animals alike. They may be of sporadic origin, acquired through exogenous introduction of infectious misfolded prion protein, or caused by genetic alterations in the prion protein coding gene. We have recently described a novel pathway linking retention of mutant prion protein in the early secretory pathway to activation p38-MAPK and a neurodegenerative phenotype in transgenic mice. Here we review the consequences that mutations in prion protein have on intracellular transport and stress responses focusing on protein quality control. We also discuss the neurotoxic signaling elicited by the accumulation of mutant prion protein in the endoplasmic reticulum and the Golgi apparatus. Improved knowledge about these processes will help us to better understand complex pathogenesis of prion diseases, a prerequisite for therapeutic strategies.