Dataset Information

Transition of the prion protein from a structured cellular form (PrP^C ) to the infectious scrapie agent (PrP^Sc ).

ABSTRACT: Prion diseases in mammals are caused by a conformational transition of the cellular prion protein from its native conformation (PrP^C ) to a pathological isoform called "prion protein scrapie" (PrP^Sc ). A molecular level of understanding of this conformational transition will be helpful in unveiling the disease etiology. Experimental structural biological techniques (NMR and X-ray crystallography) have been used to unravel the atomic level structural information for the prion and its binding partners. More than one hundred three-dimensional structures of the mammalian prions have been deposited in the protein databank. Structural studies on the prion protein and its structural transitions will deepen our understanding of the molecular basis of prion pathogenesis and will provide valuable guidance for future structure-based drug discovery endeavors.

SUBMITTER: Baral PK

PROVIDER: S-EPMC6863700 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Transition of the prion protein from a structured cellular form (PrPC ) to the infectious scrapie agent (PrPSc ).

Baral Pravas K PK Yin Jiang J Aguzzi Adriano A James Michael N G MNG

Protein science : a publication of the Protein Society 20191025 12

Prion diseases in mammals are caused by a conformational transition of the cellular prion protein from its native conformation (PrPC ) to a pathological isoform called "prion protein scrapie" (PrPSc ). A molecular level of understanding of this conformational transition will be helpful in unveiling the disease etiology. Experimental structural biological techniques (NMR and X-ray crystallography) have been used to unravel the atomic level structural information for the prio ...[more]

PMID: 31583788

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Project description:Prion diseases are fatal neurodegenerative diseases in mammals with the unique characteristics of misfolding and aggregation of the cellular prion protein (PrPC) to the scrapie prion (PrPSc). Although neuroinflammation and neuronal loss feature within the disease process, the details of PrPC/PrPSc molecular transition to generate different aggregated species, and the correlation between each species and sequence of cellular events in disease pathogenesis are not fully understood. In this study, using mice inoculated with the RML isolate of mouse-adapted scrapie as a model, we applied asymmetric flow field-flow fractionation to monitor PrPC and PrPSc particle sizes and we also measured seeding activity and resistance to proteases. For cellular analysis in brain tissue, we measured inflammatory markers and synaptic damage, and used the isotropic fractionator to measure neuronal loss; these techniques were applied at different timepoints in a cross-sectional study of disease progression. Our analyses align with previous reports defining significant decreases in PrPC levels at pre-clinical stages of the disease and demonstrate that these decreases become significant before neuronal loss. We also identified the earliest PrPSc assemblies at a timepoint equivalent to 40% elapsed time for the disease incubation period; we propose that these assemblies, mostly composed of proteinase K (PK)-sensitive species, play an important role in triggering disease pathogenesis. Lastly, we show that the PK-resistant assemblies of PrPSc that appear at timepoints close to the terminal stage have similar biophysical characteristics, and hence that preparative use of PK-digestion selects for this specific subpopulation. In sum, our data argue that qualitative, as well as quantitative, changes in PrP conformers occur at the midpoint of subclinical phase; these changes affect quaternary structure and may occur at the threshold where adaptive responses become inadequate to deal with pathogenic processes.

Dataset Information

Transition of the prion protein from a structured cellular form (PrP^C ) to the infectious scrapie agent (PrP^Sc ).

Publications

Transition of the prion protein from a structured cellular form (PrP<sup>C</sup> ) to the infectious scrapie agent (PrP<sup>Sc</sup> ).

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