The stress of prion disease

Prion diseases are fatal neurodegenerative disorders that include scrapie of sheep, bovine spongiform encephalopathy of cattle, chronic wasting disease of cervids, and Creutzfeldt-Jakob disease (CJD) of humans. The etiology for prion diseases can be infectious, sporadic, or hereditary. However, the common denominator for all types is the formation of a transmissible agent composed of a β-sheet-rich, misfolded version of the host-encoded prion protein (PrP^C), known as PrP^Sc. PrP^Sc self-replicates through a template-assisted process that converts the α-helical conformation of PrP^C into the disease-associated isoform. In parallel with PrP^Sc accumulation, spongiform change is pathologically observed in the central nervous system, where "holes" appear because of massive neuronal death. Here, we review the cellular pathways triggered in response to PrP^Sc formation and accumulation. Available data suggest that neuronal dysfunction and death may be caused by what originates as a cellular pro-survival response to chronic PrP^Sc accumulation. We also discuss what is known about the complex cross-talk between the endoplasmic reticulum stress components and the quality control pathways. Better knowledge about these processes may lead to innovative therapeutic strategies based on manipulating the stress response and its consequences for neurodegeneration. This article is part of a Special Issue entitled SI:ER stress.