Structural attributes of mammalian prion infectivity: Insights from studies with synthetic prions

Abstract

Edited by Ursula JakobPrion diseases are neurodegenerative disorders that affect many mammalian species. Mammalian prion proteins (PrPs) can misfold into many different aggregates. However, only a small subpopulation of these structures is infectious. One of the major unresolved questions in prion research is identifying which specific structural features of these misfolded protein aggregates are important for prion infectivity in vivo. Previously, two types of proteinase K-resistant, self-propagating aggregates were generated from the recombinant mouse prion protein in the presence of identical cofactors. Although these two aggregates appear biochemically very similar, they have dramatically different biological properties, with one of them being highly infectious and the other one lacking any infectivity. Here, we used several MS-based structural methods, including hydrogen-deuterium exchange and hydroxyl radical footprinting, to gain insight into the nature of structural differences between these two PrP aggregate types. Our experiments revealed a number of specific differences in the structure of infectious and noninfectious aggregates, both at the level of the polypeptide backbone and quaternary packing arrangement. In particular, we observed that a high degree of order and stability of ␤-sheet structure within the entire region between residues ϳ89 and 227 is a primary attribute of infectious PrP aggregates examined in this study. By contrast, noninfectious PrP aggregates are characterized by markedly less ordered structure up to residue ϳ167. The structural constraints reported here should facilitate development of experimentally based high-resolution structural models of infectiosus mammalian prions.

Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation

“…Taken together, the presence of protease and SDSresistant dimers detected by LC-MS/MS confirm the presence of misfolded tau, each with microtubule binding repeats protected from trypsin digestion. The extent to which different peptide fragment signatures and yields are due to the conformational diversity, differential lysine acetylation, or both, will have to be investigated with high-resolution conformationally sensitive MS tools such as hydroxyl radical footprinting and hydrogen/deuterium exchange [61].…”

“…In prion prototypes based upon PrP the misfolded form was commonly referred to as PrP Sc , the scrapie/pathologic from of PrP, but a subsequent insight was that a variety of alternative misfolded forms could account for "strain" phenomena that had already been deduced from in vivo infection experiments [12]. In the case of human prion strains, deriving from the study of Creutzfeldt-Jakob disease, the generally accepted definition and differentiation of strains is based on four necessary characteristics: (i) distinct clinical phenotype in the original host, (ii) distinct neuropathological characteristics, (iii) transmissibility and serial passage of the unique clinicopathological phenotype in experimental animals or cells expressing physiological levels of wild type PrP C , and (iv) differential conformational characteristics of prion protein determined with biophysical tools [52,61]. While the extent to which data from tauopathy models and in vitro-generated tau aggregates fulfill these criteria is vigorously debated, we have explored these concepts to arrive at an understanding of the heterogeneity present within FTLD-MAPT.…”

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

“…Apart from the autocatalytic propagation of PrP Sc , another crucial hallmark of the PrP C ‐PrP Sc conversion is the de novo generation of infectivity. However, when inoculated into animals, PrP fibrillar assemblies can range from being biologically inert to fully infectious, pathogenic, and transmissible in subsequent passages . Legname and coworkers inoculated transgenic mice expressing truncated PrP C (aa 89‐231) with amyloid fibrils formed from recombinant PrP (aa 89‐230).…”

“…However, when inoculated into animals, PrP fibrillar assemblies can range from being biologically inert to fully infectious, pathogenic, and transmissible in subsequent passages. 37,76,[193][194][195] Legname and coworkers 196 can easily occur. [200][201][202][203][204] This is supported by the finding that by releasing PrP C from the cell surface or interrupting its transport to the plasma membrane prevents the formation of PrP Sc .…”

The prion 2018 round tables (I): the structure of PrPSc

“…[5][6][7][8][9][10][11][12][13]. Recent evidence suggests that the difference between these biological effects can sometimes be correlated with conformational differences [14,15]. Collectively, the diversity of prions and prionlike PrP assemblies suggest that there may be no single PrP Sc structure, and that diversity in conformation, and even basic multimer architecture, should be anticipated.…”