Abstract
Prions are composed of the misfolded prion protein (PrPSc) organized in a variety of aggregates. An important question in the prion field has been to determine the identity of functional PrPSc aggregates. In this study, we used equilibrium sedimentation in sucrose density gradients to separate PrPSc aggregates from three hamster prion strains (Hyper, Drowsy, SSLOW) subjected to minimal manipulations. We show that PrPSc aggregates distribute in a wide range of arrangements and the relative proportion of each species depends on the prion strain. We observed a direct correlation between the density of the predominant PrPSc aggregates and the incubation periods for the strains studied. The relative presence of PrPSc in fractions of different sucrose densities was indicative of the protein deposits present in the brain as analyzed by histology. Interestingly, no association was found between sensitivity to proteolytic degradation and aggregation profiles. Therefore, the organization of PrP molecules in terms of the density of aggregates generated may determine some of the particular strain properties, whereas others are independent from it. Our findings may contribute to understand the mechanisms of strain variation and the role of PrPSc aggregates in prion-induced neurodegeneration.
Highlights
Neurodegeneration in the brain of AD patients has been suggested to better correlate with oligomeric amyloid-β (Aβ ) than amyloid plaques[21]
In order to test whether HY, DY, and SSLOW prions, having the same amino acid sequence, could be differentiated by their aggregate distribution profiles, we submitted samples from these three strains to 40–70% sucrose density gradients
The identity of prions as proteinaceous particles is widely accepted[38,49,50,51], little information is available in regards of the specific structural arrangements that the infectious agent acquires
Summary
Neurodegeneration in the brain of AD patients has been suggested to better correlate with oligomeric amyloid-β (Aβ ) than amyloid plaques[21]. In a similar manner to conventional infectious agents, prions exhibit a large strain variation, resulting in diseases with distinct clinical symptoms, incubation periods, profile of neuropathological damage and biochemical properties of the agent[29]. PrPSc associated with different strains has been shown to form distinct types of aggregates, a feature that could be connected to some of the peculiar characteristics observed for each agent[12,15]. In this sense, the presence of protease sensitive/low molecular weight structures has been linked to shorter incubation periods[12]. In this study we analyzed the aggregation profile, under conditions of minimal manipulation, of three hamster prion strains showing different clinical, histopathological and biochemical features
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