What Is Our Current Understanding of PrP^Sc-Associated Neurotoxicity and Its Molecular Underpinnings?

The prion diseases are a collection of fatal, transmissible neurodegenerative diseases that cause rapid onset dementia and ultimately death. Uniquely, the infectious agent is a misfolded form of the endogenous cellular prion protein, termed PrP^Sc. Despite the identity of the molecular agent remaining the same, PrP^Sc can cause a range of diseases with hereditary, spontaneous or iatrogenic aetiologies. However, the link between PrP^Sc and toxicity is complex, with subclinical cases of prion disease discovered, and prion neurodegeneration without obvious PrP^Sc deposition. The toxic mechanisms by which PrP^Sc causes the extensive neuropathology are still poorly understood, although recent advances are beginning to unravel the molecular underpinnings, including oxidative stress, disruption of proteostasis and induction of the unfolded protein response. This review will discuss the diseases caused by PrP^Sc toxicity, the nature of the toxicity of PrP^Sc, and our current understanding of the downstream toxic signaling events triggered by the presence of PrP^Sc.