Date Published: April 13, 2017
Publisher: Public Library of Science
Author(s): Markus Zweckstetter, Jesús R. Requena, Holger Wille, Heather L. True.
The infectious isoform of the mammalian prion protein, PrPSc, was the first protein to be identified as an infectious protein  (Table 1). PrPSc can be transmitted both from cell-to-cell and between animals or individuals and causes an invariably fatal, neurodegenerative disease . Fungal prions, which are unrelated to the mammalian prion protein, convey cytosolic inheritance based on different protein folding states and are transmitted from mother to daughter cell during cell division or in the course of cytoplasmic fusion events [3,4]. In recent years, other neurodegenerative diseases, such as Alzheimer disease and Parkinson disease, were also recognized as being spread by cell-to-cell transmission of protein aggregates, although the infectivity of these particles is a matter of debate . In these cases, proteins other than the prion protein (e.g., Aβ, microtubule-associated protein tau, α-synuclein, etc.) are prone to misfolding and aggregation (Table 1) and were subsequently labeled as prions, prionoids, or prion-like proteins, depending on the preferences of the authors and reflecting the open question with respect to infectivity .
Recent technological advances have provided a wealth of data on the structures of pathologically aggregated, infectious proteins involved in Alzheimer disease, Parkinson disease, and the prion diseases. In the former cases, the structure of the aggregated proteins (Aβ and α-synuclein) were found to adopt an in-register β-sheet structure [24,25]. In contrast, for the archetypical prion diseases (PrPSc), a four-rung β-solenoid architecture was observed [10,15], in agreement with lower-resolution approaches [18,28,31,32]. The ability to generate disease-relevant protein conformers in vitro, in combination with solid-state NMR and other analysis techniques, was crucial for determining the high-resolution structures of misfolded Aβ and α-synuclein [24,25]. A similar approach may provide high-resolution structural information about PrPSc in the future.