Abstract
Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein forms multiple, conformationally and morphologically distinct structures. Considering that such structural variations can greatly complicate the search for potential antiamyloid compounds, either by having specific propagation properties or stability, it is important to better understand this aggregation event. We have recently reported the ability of prion protein fibrils to obtain at least two distinct conformations under identical conditions, which raised the question if this occurrence is tied to only certain environmental conditions. In this work, we examined a large sample size of prion protein aggregation reactions under a range of temperatures and analyzed the resulting fibril dye-binding, secondary structure and morphological properties. We show that all temperature conditions lead to the formation of more than one fibril type and that this variability may depend on the state of the initial prion protein molecules.
Highlights
Amyloidogenic protein aggregation into insoluble, beta-sheet rich fibrils is linked with the onset of several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s or prion diseases [1,2]
Ple contained an identical concentration of prion protein and their aggregation kinetic curves reached a plateau, indicating a finished fibrillization process
Considering that a shift in sample secondary structure and the existence of high inConsidering that a shift in sample secondary structure and the existence of high intentensity samples coincide with the temperature, at which the prion protein switches besity samples coincide with the temperature, at which the prion protein switches between tween the folded and unfolded states, suggests that this factor is important in determining the folded and unfolded states, suggests that this factor is important in determining the the type of fibril conformation
Summary
Amyloidogenic protein aggregation into insoluble, beta-sheet rich fibrils is linked with the onset of several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s or prion diseases [1,2]. The way these structures form and propagate is still not fully understood, as evidence for new aggregation mechanisms or fibril structural features [3,4,5] keeps appearing on a regular basis. One of the more interesting aspects of amyloid aggregation is the ability of a single type of protein to associate into multiple conformationally-distinct fibrils [10]. Such a phenomenon was observed with prion proteins, both in vivo and in vitro [11,12,13,14] and later–
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