Comparing the Folds of Prions and Other Pathogenic Amyloids

Pathogenic amyloids are the main feature of several neurodegenerative disorders, such as Creutzfeldt⁻Jakob disease, Alzheimer’s disease, and Parkinson’s disease. High resolution structures of tau paired helical filaments (PHFs), amyloid-β(1-42) (Aβ(1-42)) fibrils, and α-synuclein fibrils were recently reported using cryo-electron microscopy. A high-resolution structure for the infectious prion protein, PrP^Sc, is not yet available due to its insolubility and its propensity to aggregate, but cryo-electron microscopy, X-ray fiber diffraction, and other approaches have defined the overall architecture of PrP^Sc as a 4-rung β-solenoid. Thus, the structure of PrP^Sc must have a high similarity to that of the fungal prion HET-s, which is part of the fungal heterokaryon incompatibility system and contains a 2-rung β-solenoid. This review compares the structures of tau PHFs, Aβ(1-42), and α-synuclein fibrils, where the β-strands of each molecule stack on top of each other in a parallel in-register arrangement, with the β-solenoid folds of HET-s and PrP^Sc.