Pathological prion protein (PrPSc) (PrPSc)

Pathological prion protein, commonly referred to as PrPSc, is the misfolded, infectious isoform of the endogenous cellular prion protein (PrPC) (Prusiner, 1982). Unlike the alpha-helix-rich PrPC, PrPSc is characterized by a high beta-sheet content, which renders it resistant to proteolysis and prone to forming insoluble oligomers and amyloid aggregates (UniProt P04156). These aggregates act as templates that induce the misfolding of healthy PrPC molecules, leading to a self-propagating neurodegenerative cascade (Aguzzi & Lakkaraju, 2016). This process is the central feature of transmissible spongiform encephalopathies (TSEs), such as Creutzfeldt-Jakob disease, where the accumulation of PrPSc causes extensive neuronal loss and spongiform changes in the brain (Scheckel & Aguzzi, 2018). Therapeutic development targets PrPSc by attempting to block its formation, accelerate its degradation, or reduce the availability of its precursor, PrPC, using antisense oligonucleotides or monoclonal antibodies (Mead et al., 2022; Minikel et al., 2020). Despite numerous efforts, treating prion diseases remains a significant challenge due to the rapid clinical decline of patients and the difficulty of delivering drugs across the blood-brain barrier (Teruya et al., 2023).

Other names

Scrapie prion proteinPrP-resPrP-dPrion protein oligomerPrion protein aggregate

Therapeutic strategies focus on reducing the levels of the cellular precursor (PrPC), stabilizing the PrPC conformation to prevent misfolding, inhibiting the conversion of PrPC to the pathological PrPSc isoform, or promoting the clearance of existing PrPSc aggregates (Minikel et al., 2020; Mead et al., 2022).