High Pressure Induces Scrapie-like Prion Protein Misfolding and Amyloid Fibril Formation†

AbstractOligomeric aggregates populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer’s disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach combining theory, experiment, and simulation, we reveal in molecular detail the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we find that most Aβ42 oligomers dissociate to their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar species. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.

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Defining the Pathway of Worm-like Amyloid Fibril Formation by the Mouse Prion Protein by Delineation of the Productive and Unproductive Oligomerization Reactions

Biochemistry ◽

10.1021/bi101757x ◽

2011 ◽

Vol 50 (7) ◽

pp. 1153-1161 ◽

Cited By ~ 25

Author(s):

Shweta Jain ◽

Jayant B. Udgaonkar

Keyword(s):

Prion Protein ◽

Amyloid Fibril ◽

Fibril Formation ◽

Amyloid Fibril Formation

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Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006684117 ◽

2020 ◽

Vol 117 (39) ◽

pp. 24251-24257 ◽

Cited By ~ 2

Author(s):

Thomas C. T. Michaels ◽

Andela Šarić ◽

Georg Meisl ◽

Gabriella T. Heller ◽

Samo Curk ◽

...

Keyword(s):

Protein Misfolding ◽

Amyloid Fibril ◽

Complex Problem ◽

Fibril Formation ◽

Amyloid Aggregation ◽

Design And Optimization ◽

Amyloid Fibril Formation ◽

Potent Inhibition ◽

General Physical ◽

Misfolding Diseases

Understanding the mechanism of action of compounds capable of inhibiting amyloid-fibril formation is critical to the development of potential therapeutics against protein-misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates, and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of amyloid-aggregation inhibition that reveals the fundamental thermodynamic and kinetic signatures characterizing effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimization of inhibitors of amyloid-fibril formation, revealing in particular the important role of on-rates in the binding of the inhibitors.

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